Compounds having effects on serotonin-related systems

ABSTRACT

A series of hetero-oxy alkanamines are effective pharmaceuticals for the treatment of conditions related to or affected by the reuptake of serotonin and by the serotonin 1 A  receptor. The compounds are particularly useful for alleviating the symptoms of nicotine and tobacco withdrawal, and for the treatment of depression and other conditions for which serotonin reuptake inhibitors are used.

CROSS REFERENCE

This application is a continuation-in-part of application Ser. No.08/373,823, now abandoned filed Jan. 17, 1995.

FIELD OF THE INVENTION

The present invention belongs to the fields of pharmacology andmedicinal chemistry, and provides new pharmaceuticals which are usefulfor the treatment of diseases which are caused or affected by disordersof the serotonin-affected neurological systems, particularly thoserelating to the serotonin 1_(A) receptor and those relating to thereuptake of serotonin.

BACKGROUND OF THE INVENTION

Pharmaceutical researchers have discovered in recent years that theneurons of the brain which contain monoamines are of extreme importancein a great many physiological processes which very strongly affect manypsychological and personality-affecting processes as well. Inparticular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be akey to a very large number of processes which affect both physiologicaland psychological functions. Drugs which influence the function ofserotonin in the brain are accordingly of great importance and are nowused for a surprisingly large number of different therapies.

The early generations of serotonin-affecting drugs tended to have avariety of different physiological functions, considered from both themechanistic and therapeutic points of view. For example, many of thetricyclic antidepressant drugs are now known to be active as inhibitorsof serotonin reuptake, and also to have anticholinergic, antihistaminicor anti-α-adrenergic activity. More recently, it has become possible tostudy the function of drugs at individual receptors in vivo or ex vivo,and it has also been realized that therapeutic agents free of extraneousmechanisms of action are advantageous to the patient. Accordingly, theobjective of research now is to discover agents which affect onlyfunctions of serotonin, for example, at a single identifiable receptor.

The present invention provides an extensive series of pharmaceuticals,some of which have highly selective activity as antagonists and partialagonists of the serotonin 1_(A) receptor.

Some of the present pharmaceuticals have a second activity as inhibitorsof reuptake of serotonin. The best-known pharmaceutical with thatefficacy is fluoxetine, and the importance of its use in the treatmentof depression and other conditions is extremely well documented andpublicized. Recent scientific articles, for example, Artigas, TIPS, 14,262 (1993), have suggested that the efficacy of a reuptake inhibitor maybe decreased by the activation of serotonin 1_(A) receptors with theresultant reduction in the firing rate of serotonin neurons.Accordingly, present research in the central nervous system is focusingon the effect of combining reuptake inhibitors with compounds whichaffect the 5HT-1_(A) receptor.

It has very surprisingly been found that a defined portion of thepresent pharmaceuticals are potent serotonin reuptake inhibitors, aswell as having effects at the 5HT-1_(A) receptor. Such compounds are notbelieved to have been known before.

SUMMARY OF THE INVENTION

The present invention provides a series of new compounds, methods ofusing them for pharmaceutical purposes, and pharmaceutical compositionswhereby the compounds may be conveniently administered. The scope of thecompounds useful in the methods is somewhat more broad than the scope ofthe novel compounds.

The invention provides the following compounds of formula I: ##STR1##wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it isattached to complete a pyrrolyl, imidazolyl, pyridinyl, pyrazinyl,pyridazinyl or pyrimidinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR2## the dotted line is an optional double bond; R¹ ispiperidinyl, piperazino, morpholino or pyrrolyl,

substituted with 0-1 phenyl or benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃alkoxy or halo groups;

which phenyl or benzyl group is substituted with 0-2 C₁ -C₃ alkyl, halo,trifluoromethyl or C₁ -C₃ alkoxy groups;

or R¹ is ##STR3## n and m are independently 4-5, and the group ofFormula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl,C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl,

substituted with pyrrolyl, furyl, thienyl, pyridinyl, morpholinyl,piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl,benzazepinyl, dibenzazepinyl or quinolinyl,

substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R² is hydroxy, hydrogen, cyano, C₁ -C₄ alkyl, or (phenyl or benzylsubstituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups);

or R² is amino substituted with phenyl or benzyl, substituted with 0-2C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo or trifluoromethyl groups;

or R² is absent when the dotted line is a double bond;

R³ is C₁ -C₄ alkyl,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R³ is C₁ -C₄ alkyl substituted with hydroxyimino or hydroxy;

or R³ is phenoxy,

substituted with 0-1 methylenedioxy or substituted with 0-2 C₁ -C₃alkyl, C₁ -C₃ alkoxy, trifluoromethyl or halo groups;

or R³ is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl, ordibenzocyclohexenyl;

or R³ is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazolyl,indolyl, benzofuryl, benzothienyl, piperidino or morpholino,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, C₄ -C₈cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxyor trifluoromethoxy groups; or substituted with 0-1 phenyl,piperidinonyl, hexahydropyridazinonyl or piperazinonyl group,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

provided that R³ is not halo- or trifluoromethyl-substituted phenyl whenR² is hydroxy;

or R² and R³ combine to form C₁ -C₄ alkylidene,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

R⁵ is C₁ -C₆ alkyl;

or R⁵ is C₁ -C₃ alkyl substituted with benzodioxinyl or benzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is pyridinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl,pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is ##STR4## B is oxygen or sulfur; Y is a residue which combineswith the atoms to which it is attached to complete a triazolyl,imidazolyl, thiazolyl or pyrrolyl ring;

A is a residue which combines with the nitrogen atom to which it isattached to complete

a) an azabicyclo(octyl, nonyl or decyl) group; ##STR5## M is a residuewhich combines with the carbon atom to which it is attached to completean indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl,dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl,benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, ornaphthodihydropyrrolyl group wherein the spiro junction is not to anaromatic ring,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- orpiperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy,phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁶ and R⁷ combine with the atom to which they are attached tocomplete a fluorenyl or dihydroanthracenyl group;

or R⁶ and R⁷ represent hydrogen, provided that p must not be 1;

q represents 0-2;

Q represents a residue which combines with the atoms to which it isattached to complete a phenyl or naphthyl group,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R⁸ is hydrogen or C₁ -C₃ alkyl;

or a pharmaceutically acceptable salt thereof.

The following genus of compounds, which is enclosed within the compoundsof formula I, have efficacy as serotonin reuptake inhibitors, as well asactivity at the 5HT-1_(A) receptor. ##STR6## wherein r is 0-3;

X is hydrogen or hydroxy;

R is ##STR7## the dotted line is an optional double bond; R² is hydroxyor hydrogen, or is absent when the dotted line is a double bond;

R³ is C₁ -C₄ alkyl,

substituted with 1-2 phenyl groups,

substituted with 0-2 halo groups;

or R³ is dibenzocycloheptenyl or benzodioxinyl;

or R³ is phenyl, benzothienyl, naphthyl, indolyl or piperidino,

substituted with 0-2 C₁ -C₃ alkoxy, hydroxy, cyano, C₁ -C₃ alkyl, C₄ -C₈cycloalkylalkoxy, halo, nitro, trifluoromethyl or trifluoromethoxygroups;

or R² and R³ combine to form C₁ -C₄ alkylidene,

substituted with 1-2 phenyl groups,

substituted with 0-2 halo groups;

provided that R³ is not halo- or trifluoromethyl-substituted phenyl whenR² is hydroxy;

A is a residue which combines with the nitrogen atom to which it isattached to complete ##STR8## M is a residue which combines with thecarbon atom to which it is attached to complete a benzopyranyl,naphthodihydrofuranyl, benzodihydrothienyl, or benzodihydrofuranylgroup, wherein the spiro junction is not to an aromatic ring,

substituted with 0-2 C₁ -C₃ alkoxy, benzyloxy, phenyl or halo groups;

or a pharmaceutically acceptable salt thereof.

The invention also provides pharmaceutical compositions comprising theabove compounds.

Pharmaceutical methods of use are provided by the invention, whichmethods comprise the administration to patients in need of such methodsof use of a compound of the following formula. ##STR9## wherein r is0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it isattached to complete a pyrrolyl, imidazolyl, pyridinyl, pyrazinyl,pyridazinyl or pyrimidinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR10## the dotted line is an optional double bond; R¹ ispiperidinyl, adamantyl, piperazino, morpholino or pyrrolyl,

substituted with 0-1 phenyl or benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃alkoxy or halo groups;

which phenyl or benzyl group is substituted with 0-2 C₁ -C₃ alkyl, halo,trifluoromethyl or C₁ -C₃ alkoxy groups;

or R¹ is ##STR11## n and m are independently 4-5, and the group ofFormula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl,C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl,

substituted with pyrrolyl, adamantyl, furyl, thienyl, pyridinyl,morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl,tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinolinyl,

substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R² is hydroxy, hydrogen, cyano, C₁ -C₄ alkyl, or (phenyl or benzylsubstituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups);

or R² is amino substituted with phenyl or benzyl,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

or R² is absent when the dotted line is a double bond;

R³ is C₁ -C₄ alkyl,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R³ is C₁ -C₄ alkyl substituted with hydroxyimino or hydroxy;

or R³ i s phenoxy,

substituted with 0-1 methylenedioxy or substituted with 0-2 C₁ -C₃alkyl, C₁ -C₃ alkoxy, trifluoromethyl or halo groups;

or R³ is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl, ordibenzocyclohexenyl;

or R³ is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazolyl,indolyl, benzofuryl, benzothienyl, piperidino or morpholino,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, C₄ -C₈cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxyor trifluoromethoxy groups; or substituted with 0-1 phenyl,piperidinonyl, hexahydropyridazinonyl or piperazinonyl group,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

or R² and R³ combine to form C₁ -C₄ alkylidene,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl;

or R⁵ is C₁ -C₃ alkyl substituted with phenyl, benzodioxinyl orbenzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is pyridinyl, phenyl, naphthyl, tetralinyl, pyrimidinyl, indolyl,benzofuryl, benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl,pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is ##STR12## B is oxygen or sulfur; Y is a residue which combineswith the atoms to which it is attached to complete a triazolyl,imidazolyl, thiazolyl or pyrrolyl ring;

A is a residue which combines with the nitrogen atom to which it isattached to complete

a) an azabicyclo(octyl, nonyl or decyl) group; ##STR13## M is a residuewhich combines with the carbon atom to which it is attached to completean indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl,dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl,benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, ornaphthodihydropyrrolyl group wherein the spiro junction is not to anaromatic ring,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- orpiperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy,phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁶ and R⁷ combine with the atom to which they are attached tocomplete a fluorenyl or dihydroanthracenyl group;

or R⁶ and R⁷ represent hydrogen, provided that p must not be 1;

q represents 0-2;

Q represents a residue which combines with the atoms to which it isattached to complete a phenyl or naphthyl group,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R⁸ is hydrogen or C₁ -C₃ alkyl;

or a pharmaceutically acceptable salt thereof.

Further, pharmaceutical methods of use combining activity at the 1_(A)receptor and inhibition of serotonin reuptake are carried out by theadministration of compounds of the following formula. ##STR14## whereinr is 0-3;

X is hydrogen or hydroxy;

R is ##STR15## the dotted line is an optional double bond; R² is hydroxyor hydrogen, or is absent when the dotted line is a double bond;

R³ is C₁ -C₄ alkyl,

substituted with 1-2 phenyl groups,

substituted with 0-2 halo groups;

or R³ is dibenzocycloheptenyl or benzodioxinyl;

or R³ is phenyl, benzothienyl, naphthyl, indolyl or piperidino,

substituted with 0-2 C₁ -C₃ alkoxy, hydroxy, C₁ -C₃ alkyl, cyano, C₄ -C₈cycloalkylalkoxy, halo, nitro, trifluoromethyl or trifluoromethoxygroups;

or R² and R³ combine to form C₁ -C₄ alkylidene,

substituted with 1-2 phenyl groups,

substituted with 0-2 halo groups;

R⁵ is phenyl, phenyl-C₁ -C₃ alkyl, or diphenyl-C₁ -C₃ alkyl,

substituted with 1-2 halo, C₁ -C₃ alkoxy or trifluoromethyl groups;

A is a residue which combines with the nitrogen atom to which it isattached to complete ##STR16## M is a residue which combines with thecarbon atom to which it is attached to complete a benzopyranyl,naphthodihydrofuranyl, benzodihydrothienyl, or benzodihydrofuranylgroup, wherein the spiro junction is not to an aromatic ring,

substituted with 0-2 C₁ -C₃ alkoxy, benzyloxy, phenyl or halo groups;

or a pharmaceutically acceptable salt thereof.

Still further, the invention provides a method of affecting theserotonin 1_(A) receptor which comprises administering to a subject inneed of such treatment an effective amount of a compound of Formula XII.More specific methods of treatment include a method of alleviating thesymptoms caused by withdrawal or partial withdrawal from the use oftobacco or of nicotine; a method of treating anxiety; and a method oftreating a condition chosen from the group consisting of depression,hypertension, cognitive disorders, psychosis, sleep disorders, gastricmotility disorders, sexual dysfunction, brain trauma, memory loss,eating disorders and obesity, substance abuse, obsessive-compulsivedisease, panic disorder and migraine; which methods compriseadministering to a subject in need of such treatment an effective amountof a compound of Formula XII. Further, the invention provides a methodof alleviating the symptoms caused by withdrawal or partial withdrawalfrom the use of tobacco or of nicotine; and a method of potentiating theaction of a serotonin reuptake inhibitor in increasing the availabilityof serotonin, norepinephrine and dopamine in the brain, comprisingadministering to a subject in need of such treatment a compound ofFormula XII in combination with a serotonin reuptake inhibitor.

The invention also provides a method of inhibiting the reuptake ofserotonin which comprises administering to a subject in need of suchtreatment an effective amount of a compound of Formula XIII; a method ofinhibiting the reuptake of serotonin wherein the serotonin 1_(A)receptor of the subject is also affected is further provided byadministering an effective amount of one of the same compounds.

Methods of treating depression and of treating both anxiety anddepression are also provided by administering to a subject in need ofsuch treatment an effective amount of a compound of Formula XIII.

Further, the administration of a compound of Formula XIII also providesa method of treating a condition chosen from the group consisting ofobsessive-compulsive disease, obesity, migraine, pain, particularlyneuropathic pain, bulimia, premenstrual syndrome or late lutealsyndrome, alcoholism, tobacco abuse, panic disorder, anxiety,post-traumatic stress disorder, memory loss, dementia of aging, socialphobia, attention-deficit hyperactivity disorder, disruptive behaviordisorders, impulsive control disorders, borderline personality disorder,chronic fatigue syndrome, premature ejaculation, erectile difficulty,anorexia nervosa, disorders of sleep, autism, mutism andtrichotilomania.

DESCRIPTION OF PREFERRED EMBODIMENTS

In the present document, all descriptions of concentrations, amounts,ratios and the like will be expressed in weight units unless otherwisestated. All temperatures are in degrees Celsius.

The Compounds

It is believed that the general description of the compounds above issufficient to explain their nature to the skilled reader; attention tothe Examples which follow is also encouraged. Some additionaldescription will be provided to assure that no misunderstanding occurs.

In the general description, the general chemical terms are all used intheir normal and customary meanings. For example, the small alkyl andalkoxy groups include, depending on the size of the groups, methyl,ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl,3-methylbutyl, hexyl, and branched hexyl groups, and the correspondingalkoxy groups, as may be allowed by the individually named groups. Wherea number of possible substituent groups are permitted on a group, suchas the 0-4 alkyl, alkoxy or halo groups permitted on an R¹ morpholinogroup, it will be understood by the reader that only substitution whichis chemically, electronically and sterically feasible is intended.

The term halo is used in the above formula to refer to fluoro, chloro,bromo or iodo.

Group D completes a bicyclic nitrogen-containing heterocycle which, mostoften, is indolyl, but may also be quinolinyl, isoquinolinyl,benzimidazolyl, quinazolinyl and the like.

The subscripts r and s indicate that as many as 7 methylene groups maybe in the linker alkylene chain. Thus, the chain is straight-chain alkylfrom ethyl through heptyl, which may be substituted with the group X asshown. The preferred groups are hydrogen and hydroxy.

The term C₄ -C₈ cycloalkylalkoxy includes groups such ascyclopropylmethoxy, cyclohexylethoxy, cyclopentylmethoxy and the like.

In the above formula, the components of the compounds, for example, thegroup of Formula IV, are illustrated in a manner which shows the pointof attachment to the basic structure. In Formula IV, for example, theattachment must be at the 1-position of the piperazinyl ring, and thesubstituent R⁵ is at the 4-position.

The group of Formula III is a piperidine or tetrahydropyridine with theR² and R³ groups at the 4-position, and an optional R⁸ group at anyother position of the ring. While the R³ group may represent any ofseveral definitions, the R² and R³ groups are both relatively simple andthe reader will readily understand the nature of them. It should benoted, however, that the novel compounds of the present invention do notinclude certain combinations of R² and R³ substituents, as explainedabove in the Summary of the Invention.

It may be noted again that bulky R³ groups such as dibenzocyclohepteneor naphthyl may be linked in any reasonable orientation, as maysubstituent parts of the R³ group such as piperazinonyl.

Where the orientation of a group is not stated, for example, a pyrrolylgroup substituted on alkyl in the definition of R¹, it is intended thatany reasonable orientation be used. The pyrrolyl group, thus, may besubstituted at the 2- or 3-positions, and may itself be substituted atwill with alkyl, alkoxy or halo groups. Again, there is no intent todescribe unreasonable or impossible substituted groups.

The spiro-linked group of Formula VI represents structures of which thefollowing are typical: ##STR17##

The fused aryl heterocyclic group of Formula VII represents, forexample, the following structures. ##STR18##

The group of Formula V has four definitions, of which the group ofFormula VIII is preferred. Formula VIII represents a spiro structurewherein M represents the atoms necessary to complete one of thedesignated cyclic groups. Several of the M groups are multiple ringstructures, such as naphthodihydropyrrolyl, wherein one or more of therings is aromatic and one is not aromatic. The skilled reader will ofcourse understand that the spiro junction necessarily is formed by aring of the M group which is not aromatic. For example, thedihydropyrrolyl group in naphthodihydropyrrolyl must form the spirojunction.

The non-aromatic ring of such M groups may be oriented in any feasiblemanner that does not place the hetero atom at the spiro junction. Somenomenclatural schemes would describe a benzodihydrothienyl group as onewhere the sulfur atom is at the 1-position and would term itisodihydrobenzothienyl if the sulfur atom is at the 2-position. In thepresent document, however, all such compounds are termedbenzodihydrothienyl, and the position of the sulfur atom is indicated bya number in the chemical name. The same principle of nomenclature isapplied in naming all of the M groups. The examples below illustratenumerous typical M groups, and several of the complex, and especiallythe spiro, R groups are drawn in the examples to assure comprehension.

Where a cyclic structure is substituted with an oxo group, as forexample a group of Formula VIII substituted with oxo, it will beunderstood that the oxo group may not occupy an aromatic ring of thecyclic structure. It will also be understood that such groups may formtautomeric structures, where the oxygen is in the hydroxy form and adouble bond is formed within the cyclic structure.

The examples below show the synthesis of numerous compounds having aspiro M group. It will be seen that one group of preferred suchcompounds includes those where the spiro ring is dihydrofuran,frequently carrying an oxo group, and fused to a phenyl or naphthylgroup. It will be understood that in each case the designation of apreferred compound here includes its pharmaceutically acceptable salts.Appropriate substituents on such compounds, particularly on the phenylor naphthyl portion of the group, include alkoxy, benzyloxy and halo.

The spiro-fused group of Formula VIII represents groups such as thefollowing. Again, it is intended that the heterocyclic groups formed bythe group completed by M may be arranged in any feasible orientation,provided that an aromatic group may not form the spiro junction, andthere is no intention to describe impossible groups or those whichcannot be synthesized by the knowledgeable organic chemist. ##STR19##

The group of Formula IX is a polymethyleneimino of from 4 to 6 methylenegroups, having the R⁶ and R⁷ substituents on the same carbon atom. Thosesubstituents may represent phenyl or substituted phenyl groups orhydrogen, or R⁶ and R⁷ may combine to form a spiro-linked fluorenyl ordihydro anthracenyl group.

The group of Formula X is a polymethylene group of 4 to 6 methylenegroups, fused to a phenyl or naphthyl group.

The compounds of Formulae XI and XIII constitute a particular class ofthe compounds described in this document, which are unique in their dualactivity as antagonists at the 5-HT₁ A receptor and inhibitors ofserotonin reuptake. It will be seen that the dual activity compounds areenclosed within Formulae I and XII and are described in the same manneras are the broader groups of compounds. It will be noted that thecompounds of Formula XIII include a class wherein the group R is apiperazine of Formula IV, which is not included within the compounds ofFormula XI, and accordingly the R⁵ group of Formula IV is also includedin Formula XIII.

The compounds described in this document are highly active, importantand particularly useful in the treatment methods of the presentinvention, but certain classes of the compounds are preferred. Thefollowing paragraphs describe such preferred classes. It will beunderstood that the preferred classes are applicable both to thetreatment methods and to the new compounds of the present invention,except where a certain class is included only in a treatment methodgenus, and not in a definition of new compounds. It will be furtherunderstood that when a certain group is referred to as preferred, itsallowable substitutions are also intended; for example, the preferredclass, R¹ is C₁ -C₄ alkyl substituted with adamantyl, is to beunderstood as including the possible alkyl, alkoxy or halo substitutionsshown in the general formula.

The first group of preferred classes of compounds is applicable to thecompounds of Formulae XI and XIII.

1) r is 1-2;

2) r is 1;

3) X is hydrogen;

4) X is hydroxy;

5) R is of Formula III;

6) R is of Formula IV;

7) R is of Formula V;

8) the dotted line does not represent a double bond and R² is hydrogen;

9) R³ is C₁ -C₂ alkyl substituted with 1-2 phenyl groups;

10) R³ is phenyl or naphthyl;

11) R³ is benzothienyl or indolyl;

12) R³ is piperidino;

13) R³ is benzothienyl substituted with 1-2 C₁ -C₃ alkoxy, C₁ -C₃ alkyl,C₄ -C₈ cycloalkylalkoxy, halo, nitro, trifluoromethyl ortrifluoromethoxy groups;

14) R³ is indolyl substituted with 1-2 C₁ -C₃ alkoxy, C₁ -C₃ alkyl, C₄-C₈ cycloalkylalkoxy, halo, nitro, trifluoromethyl or trifluoromethoxygroups;

15) M completes a benzopyranyl group;

16) M completes a naphthodihydrofuranyl group;

17) M completes a benzodihydrothienyl group;

18) M completes a benzodihydrofuranyl group;

19) the group completed by M is substituted with 1-2 alkoxy or benzyloxygroups;

20) the group completed by M is substituted with 1-2 phenyl groups;

21) the group completed by M is substituted with 1-2 alkoxy, benzyloxyor halo groups;

22) R⁵ is phenyl;

23) R⁵ is phenyl-C₁ -C₃ alkyl;

24) the group completed by M is diphenyl-C₁ -C₃ alkyl;

25) the compound is a pharmaceutically acceptable salt.

The following preferred definitions apply to the compounds of Formulae Iand XII.

a) X is hydroxy;

b) X is hydrogen;

c) R¹ is piperidinyl, piperazino, morpholino or pyrrolyl;

d) R¹ is adamantyl;

e) R¹ is a group of Formula VI;

f) R¹ is C₁ -C₂ alkyl substituted with pyrrolyl, adamantyl, furyl,thienyl, pyridinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl,piperazinyl, tetrahydrofuryl, benzazepinyl, dibenzazepinyl orquinolinyl;

g) R¹ is C₁ -C₄ alkyl substituted with adamantyl;

h) R¹ is C₁ -C₄ alkyl substituted with pyrrolyl, furyl, thienyl,benzazepinyl or dibenzazepinyl;

i) R¹ is C₁ -C₄ alkyl substituted with pyridinyl, morpholinyl,piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl orquinolinyl;

j) R² is hydroxy or hydrogen;

k) R² is cyano, alkyl, or (phenyl or benzyl substituted with 0-2 alkyl,alkoxy or halo groups);

l) R² is hydroxy;

m) R³ is alkyl substituted with phenyl;

n) R³ is phenoxy;

o) R³ is phenyl;

p) R³ is naphthyl or piperidino;

q) R³ is phenyl, substituted with alkyl, alkoxy, alkylenedioxy, halo,trifluoromethyl or trifluoromethoxy;

r) R⁵ is alkyl;

s) R⁵ is alkyl substituted with benzodioxinyl, phenyl or benzodioxolyl;

t) R⁵ is pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl,phenyl, pyridazinyl or quinazolinyl;

u) R⁵ is pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl,pyridazinyl or quinazolinyl;

v) R is a group of Formula II;

w) R is a group of Formula III;

x) R is a group of Formula IV;

y) R is a group of Formula V;

z) R⁵ is a group of Formula VII;

aa) A is a group of Formula VIII;

ab) A is a group of Formula IX;

ac) A is a group of Formula X;

ad) M completes a benzopyranyl, benzodihydropyranyl,naphthodihydrofuranyl or benzodihydrofuranyl group;

ae) M completes a benzodihydrothienyl or naphthodihydrothienyl group;

af) M completes a pyrrolidinyl, dihydroindolyl, ornaphthodihydropyrrolyl group;

ag) M completes an indanyl, indenyl, or tetralinyl group;

ah) the compound is a salt;

ai) halo is chloro, bromo or fluoro;

aj) the dotted line does not represent a double bond and R² is present;

ak) D completes a pyrrolyl group;

al) D completes an imidazolyl group;

am) D completes a pyridinyl group;

an) D completes a pyrazinyl, pyridazinyl or pyrimidinyl group;

ao) r is 1-3;

ap) r is 1;

aq) X is hydrogen, hydroxy or methoxy;

ar) X is hydrogen or hydroxy;

as) R¹ is tetralinyl or naphthyl;

at) R³ is benzodioxolyl or benzodioxinyl;

au) R³ is naphthyl or tetralinyl;

av) R³ is tetrazolyl or benzimidazolyl;

aw) R³ is indolyl, benzofuryl or benzothienyl;

ax) R³ is indolyl substituted with 1-2 alkyl, alkoxy, cycloalkylalkoxy,halo, nitro, trifluoromethyl, difluoromethyl, hydroxy ortrifluoromethoxy groups;

ay) R³ is benzothienyl substituted with 1-2 alkyl, alkoxy,cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxyor trifluoromethoxy groups;

az) R⁵ is naphthyl or tetralinyl;

ba) R⁵ is indolyl;

bb) R⁵ is benzofuryl or benzothienyl;

bc) R⁵ is quinolinyl or isoquinolinyl;

bd) the group completed by M is substituted with 0-2 alkyl, oxo, alkoxy,phenyl or halo groups;

be) the group completed by M is substituted with 0-2 alkoxy, phenoxy orbenzyloxy groups;

bf) the group completed by M is substituted with pyrrolidinyl- orpiperidinyl-C₁ -C₃ alkoxy groups;

bg) s is 0.

Further, a preferred class of compounds of Formula I includes thefollowing subgenus. ##STR20## wherein X is hydrogen, hydroxy or methoxy;R is ##STR21## R¹ is piperidinyl, piperazino, morpholino or pyrrolyl,substituted with 0-1 benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo groups;

or R¹ is ##STR22## n and m are independently 4-5, and the group ofFormula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl,C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl,

substituted with pyrrolyl, furyl, thienyl, pyridinyl, morpholinyl,piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl,benzazepinyl, dibenzazepinyl or quinolinyl,

substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R² is hydroxy, hydrogen, cyano, C₁ -C₄ alkyl, or (phenyl or benzylsubstituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups);

R³ is C₁ -C₄ alkyl,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R³ is phenoxy,

substituted with 0-1 methylenedioxy or substituted with 0-2 C₁ -C₃alkyl, C₁ -C₃ alkoxy, trifluoromethyl or halo groups;

or R³ is dibenzocycloheptene or dibenzocyclohexene;

or R³ is phenyl, naphthyl, piperidino or morpholino,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo, C₁ -C₂alkylenedioxy, trifluoromethyl, hydroxy or trifluoromethoxy groups;

or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl orpiperazinonyl group,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

provided that R³ is not halo- or trifluoromethyl-substituted phenyl whenR² is hydroxy;

R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl;

or R⁵ is C₁ -C₃ alkyl substituted with benzodioxinyl or benzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl,pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is ##STR23## B is oxygen or sulfur; Y is a residue which combineswith the atoms to which it is attached to complete a triazolyl,imidazolyl, thiazolyl or pyrrolyl ring;

A is a residue which combines with the nitrogen atom to which it isattached to complete

a) an azabicyclo(octyl, nonyl or decyl) group; ##STR24## M is a residuewhich combines with the carbon atom to which it is attached to completean indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl,dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl,benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, ornaphthodihydropyrrolyl group wherein the spiro junction is not to anaromatic ring,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, phenyl or halogroups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁶ and R⁷ combine with the atom to which they are attached tocomplete a fluorenyl or dihydroanthracenyl group;

or R⁶ and R⁷ represent hydrogen, provided that p must not be 1;

q represents 0-2;

Q represents a residue which combines with the atoms to which it isattached to complete a phenyl or naphthyl group,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R⁸ is hydrogen or C₁ -C₃ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred aspect of the invention includes methods of use of thecompounds of Formula XII described by the following subgenus. ##STR25##wherein X is hydrogen, hydroxy or methoxy; R is ##STR26## R¹ ispiperidinyl, adamantyl, piperazino, morpholino or pyrrolyl, substitutedwith 0-1 benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R¹ is ##STR27## n and m are independently 4-5, and the group ofFormula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl,C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl,

substituted with pyrrolyl, adamantyl, furyl, thienyl, pyridinyl,morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl,tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinolinyl,

substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R² is hydroxy, hydrogen, cyano, C₁ -C₄ alkyl, or (phenyl or benzylsubstituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups);

R³ is C₁ -C₄ alkyl,

substituted with 0-2 phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R is benzimidazolyl or indolyl,

substituted with 0-2 phenyl, oxo, C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halogroups;

or R³ is phenoxy,

substituted with 0-1 methylenedioxy or substituted with 0-2 C₁ -C₃alkyl, C₁ -C₃ alkoxy, trifluoromethyl or halo groups;

or R³ is dibenzocycloheptene or dibenzocyclohexene;

or R³ is phenyl, naphthyl, piperidino or morpholino,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy, halo, C₁ -C₂alkylenedioxy, trifluoromethyl, hydroxy or trifluoromethoxy groups;

or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl orpiperazinonyl group,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, halo ortrifluoromethyl groups;

R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl;

or R⁵ is C₁ -C₃ alkyl substituted with benzodioxinyl, phenyl orbenzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl,phenyl, pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy orhalo groups;

or R⁵ is ##STR28## B is oxygen or sulfur; Y is a residue which combineswith the atoms to which it is attached to complete a triazolyl,imidazolyl, thiazolyl or pyrrolyl ring;

A is a residue which combines with the nitrogen atom to which it isattached to complete

a) an azabicyclo(octyl, nonyl or decyl) group; ##STR29## M is a residuewhich combines with the carbon atom to which it is attached to completean indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl,dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl,benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, ornaphthodihydropyrrolyl group wherein the spiro junction is not to anaromatic ring,

substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, phenyl or halogroups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁶ and R⁷ combine with the atom to which they are attached tocomplete a fluorenyl or dihydroanthracenyl group;

or R⁶ and R⁷ represent hydrogen, provided that p must not be 1;

q represents 0-2;

Q represents a residue which combines with the atoms to which it isattached to complete a phenyl or naphthyl group,

substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

R⁸ is hydrogen or C₁ -C₃ alkyl;

or a pharmaceutically acceptable salt thereof.

The above compounds are used in methods of affecting, particularlymethods of antagonizing, the 5HT-1_(A) receptor, and therapeutic methodswhich are related to their effect on the 5HT-1_(A) receptor. Suchmethods of treatment include, particularly, methods of alleviating thesymptoms caused by withdrawal or partial withdrawal from the use oftobacco or of nicotine, comprising the administration to a patient inneed of such treatment of a compound of Formula I.

Further, such therapeutic methods include methods of treatment ofanxiety, depression, hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, eating disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine. A furthersuch method is the enhancement of the action of a serotonin reuptakeinhibitor by administering a compound of the above subgenus incombination with the reuptake inhibitor.

The reader will understand that the above preferred classes of compoundsmay be combined to form additional, broader or narrower classes ofpreferred compounds.

Certain compounds of the present invention are particularly active orselective, and are accordingly even more highly preferred than othercompounds and classes of compounds. The most highly preferred compoundsfor use in creating desired effects at the 5-HT₁ A receptor are thecompounds of Examples 63, 71, 78, 79, 82, 88, 94, 126 and 189 in thesection immediately following. The most highly preferred compounds withdual activity at the 1_(A) receptor and also as serotonin reuptakeinhibitors, include the compounds of Examples 64, 89, 193, 197, 196,205, 154 and 151.

Since the compounds of this invention are basic in nature, theyaccordingly react with any of a number of inorganic and organic acids toform pharmaceutically acceptable acid addition salts. Since some of thefree amines of the compounds of this invention are typically oils atroom temperature, it is preferable to convert the free amines to theirpharmaceutically acceptable acid addition salts for ease of handling andadministration, since the latter are routinely solid at roomtemperature. Acids commonly employed to form such salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, subcrate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid or maleic acid.

Many of the compounds of Formula I can form optical isomers. Inparticular, the compounds wherein X is hydroxy or methoxy have anasymmetric center at the carbon atom to which X is attached. Further,many of the R groups can exist in multiple optical forms. In general, itis preferred for the asymmetric center to which X is attached to existin the S-(-) form. However, when a compound of the present invention isnamed without an indication of asymmetric form, any and all of thepossible asymmetric forms are intended.

Synthesis

The synthesis of the present compounds is carried out by methods whichare conventional for the synthesis of related known compounds. Thesyntheses, in general, comprise the reaction of one intermediate whichsupplies the Het-oxypropane group with an intermediate which suppliesthe amine group R. The term Het will be used here to refer briefly tothe group ##STR30##

When a compound where X is hydroxy is to be prepared, the most usefulintermediate is 4-oxiranylalkoxy-Het, which is readily reacted with theamine compound which provides the R group. The oxiranyl intermediate isreadily prepared by known methods as the racemate or either enantiomer.When a compound where R is of Formula II is to be prepared, the reactantis a simple amine, such as adamantylamine; when a more complex group isto be prepared, the oxiranyl group readily reacts with the nitrogen ofthe appropriate heterocycle to prepare the desired product in goodyield. Moderate reaction conditions, such as from ambient temperature toabout 100°, are satisfactory, and any solvent which is inert to thereactants and has adequate solvency for them may be used. It has beenfound that a preferred reaction condition is the reflux temperature atambient pressure in an alcohol such as methanol. No catalyst oractivating agent is necessary, and conventional isolation procedures areeffective. The examples below illustrate the synthesis of many compoundsof the present invention by such processes. When the process is carriedout with intermediates in a single asymmetric form, little or noracemization has been observed, so that the products are obtained in thedesired single asymmetric form.

Another convenient method of synthesis of the present compounds is byuse of a 1-chloro(Het-oxy)alkane, which may optionally be substitutedwith a phenyl, hydroxy or methoxy group. Alternatively, other leavinggroups besides chloro may be used on the Het-oxyalkane, of course, suchas sulfonates, particularly methane-sulfonate or toluenesulfonate,bromo, and the like. The Het-oxyalkane intermediate is reacted with theamine-containing intermediate which provides the R group, in thepresence of any convenient acid scavenger. The usual bases such asalkali metal or alkaline earth metal carbonates, bicarbonates andhydroxides are useful acid scavengers, as are some organic bases such astrialkylamines and trialkanolamines. The reaction medium for suchreactions may be any convenient organic solvent which is inert to thebasic conditions; acetonitrile, esters such as ethyl acetate and thelike and halogenated alkane solvents are useful, as organic chemistswill readily understand. Usually the reactions will be carried out atelevated temperatures such as from ambient temperature to the refluxtemperature of the reaction mixture, particularly from about 50° toabout 100°.

Methods of synthesis of the Her intermediates are found in theliterature, together with methods of preparing the isolated enantiomersthereof, and the reader will require no assistance to obtain them.

Intermediates where X is methoxy, (Het-oxy)methoxyalkanes, are bestprepared from a dimethyl methoxyalkanedioic acid, which is first treatedwith lithium aluminum hydride to obtain, after quenching of excessreagent, a dihydroxymethoxyalkane. That intermediate is converted to theditosylate, which is reacted with hydroxy-Het to prepare the desiredintermediate having a tosyl protecting group at the terminus of thealkane. Reaction with the intermediate providing the R group is carriedout as usual with that intermediate.

Similarly, the intermediates which provide the amine-containing R groupsare all prepared by conventional procedures which may be found in theliterature. Particular mention will be made of the spiro groups ofFormula V where A is of Formula VIII, which are somewhat unusual.Methods for their preparation are found in the literature, and thefollowing articles are pointed out as useful.

Marxer, et al., J. Org. Chem., 40, 1427-1433, (1975)

Parham, et al., J. Org. Chem., 41, 2628-2635, (1976)

Yamato, et al., J. Med. Chem., 24, 194-198, (1981)

Evans, et al., J. Med. Chem., 35, 3919-3927, (1992)

Efange, et al., J. Med. Chem., 37, 2574-2582, (1994)

Chambers, et al., J. Med. Chem., 35, 2033-2039, (1992)

The spiropiperidine intermediates are prepared, in general, by reactionof a 4-piperidinone or a piperidine having an activated group at the4-position with a reagent which can attack the 4-position of thepiperidine and form the necessary cyclic structure. For example, whenthe group attached spiro to the piperidine is a dihydrofuran ring, thestarting material is an N-alkylated-4-piperidinone, which is reactedwith an N,N-disubstituted benzamide or naphthylamide, carrying thedesired substituents on the phenyl or naphthyl rings. The amide is firstreacted with an alkyllithium reagent to form the metallated derivative.Reaction of that derivative with the piperidinone results in attack atthe ketone of the piperidinone. A second step of quenching with a protonsource, particularly with a dilute mineral acid, cyclizes thedihydrofuran ring, leaving it with an oxo group appended. The productmay be reduced, as by treatment with a borane, if desired, and thenitrogen of the piperidine is dealkylated with excess1-chloroethylchloroformate. The spiro intermediate is then reacteddirectly with the indole intermediate.

When the group joining the piperidine is a dihydrothienyl group, theprocess for synthesis is similar, but the starting material is a phenylor naphthyl compound having a 1-mercaptomethyl group. A bromine or otherstrong leaving group is ortho to the mercaptomethyl group. Reaction withthe piperidinone, followed by quenching with either a Lewis or proticacid, produces the desired benzodihydrothienyl or naphthodihydrothienylspiro group. The process for preparing pyran and dihydropyran spirogroups proceeds substantially the same, but starting with a compoundhaving a 1-hydroxymethyl rather than a 1-mercaptomethyl group.

Substituents on the spiropiperidine groups of Formula VIII, if notoriginating with the phenyl or naphthyl starting material, may be placedin later steps according to conventional processes.

Spiro compounds of Formula VIII which comprise an indanyl, indenyl ortetralinyl group are prepared directly from the corresponding indane,indene or tetralin which is activated at the desired point of attachmentby formation of a salt, by treatment with a strong base such aspotassium hexamethyldisilylamide, which is reacted withdi(2-chloroethyl)amine, carrying a protecting group such ast-butoxycarbonyl on the nitrogen. The desired spiropiperidine isproduced in a single step, but retaining the protecting group on thenitrogen of the piperidine. Deprotection by conventional means producesthe desired intermediate.

Similarly, spiro intermediates having a pyrrolidinyl, dihydroindolinylor naphthodihydropyrrolyl group are made by reacting a 2-oxopyrrolidinehaving a protecting group on the nitrogen, such as t-butoxycarbonyl,with protected di(2-chloroethyl)amine. The desired spiropiperidine, withan oxo group on the 5-membered ring and the protecting group on thepiperidine nitrogen is obtained. Deprotection is conventional, and theoxo may be reduced, if desired, with lithium aluminum hydride or anotherconventional agent. The following Preparations illustrate the synthesisof such intermediates further.

The important group of compounds where R is a piperidine ortetrahydropyridine of Formula III, and R³ is a cyclic group such asnaphthyl or indole, are readily prepared by first making the R groupcomplete, protecting the nitrogen of the piperidine ortetrahydropyridine as necessary during the synthesis, and reacting itwith either an oxiranyl intermediate, or an alkoxy-Het bearing a chloroatom or other leaving group, as described above.

Thus, the general process for preparing the present compounds has twomain variations, which may briefly be described as follows: ##STR31##

It is believed that all chemical names used here are unambiguous.However, drawings of the various complex R groups are given with theexample in which each exemplified complex structure appears for thefirst time.

In the following Examples and Preparations, the abbreviation FDMS meansfield desorption mass spectroscopy.

The first group of Preparations illustrates typical syntheses ofspiropiperidine intermediates used for preparing compounds where R is ofFormula V and A is of Formula VIII.

Preparation 1 Preparation of4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one

A three-neck flask was charged with 2-methoxy-N,N-diethylbenzamide(11.45 g., 55.3 mmol), 90 mL tetrahydrofuran (THF) andN,N,N',N'-tetramethylethylenediamine (TMEDA) (1.0 equivalent). Themixture was cooled to -78° C., and s-butyllithium (1.5 equiv. of a 1.3Msolution in cyclohexane) was added dropwise, and the mixture was stirredfor one hour. A solution of 1-methyl-4-piperidone (6.57 g. 1 equiv.) in45 mL of THF was slowly added, at low temperature. The cooling bath wasremoved, and the mixture allowed to stir, at room temperature, for 12 h.5N hydrochloric acid (60 mL) was added, and the aqueous and organiclayers were separated. The organic layer was washed again with 1Nhydrochloric acid, the aqueous layers were combined and treated withsaturated aqueous ammonium hydroxide solution, and extracted intochloroform. The organic layer was washed with brine, and dried oversodium sulfate. The mixture was concentrated and purified by silica gelcolumn chromatography (2-5% methanol in dichloromethane eluent gradient)to provide the N-methylated derivative of the title compound. It wasdissolved in 1,2-dichloroethane, cooled to 0° C., and treated withexcess 1-chloroethylchloroformate, allowed to warm to room temperature,and then heated at reflux for 12 hours. The mixture was cooled to 0° C.and concentrated in solution, methanol (50 mL) was added, and heatingwas continued for 3.5 additional hours, after which time the mixture wascooled to room temperature, diluted with water, treated with saturatedaqueous ammonium hydroxide solution, and extracted into chloroform. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, concentrated, and purified by silica gel column chromatography(2% methanol in dichloromethane) to give 4.5 g (31% yield over twosteps) of the title compound as a waxy solid. FDMS (m/e=233).

Preparation 2 Preparation of4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]

A three-neck flask was charged with 2-methoxy-N,N-diethylbenzamide(11.45 g., 55.3 mmol), 90 mL tetrahydrofuran (THF) andN,N,N',N'-tetramethylethylenediamine (TMEDA) (1.0 equivalent). Themixture was cooled to -78° C., and s-butyllithium (1.5 equiv. of a 1.3Msolution in cyclohexane) was added dropwise, and the mixture was stirredfor one hour. A solution of 1-methyl-4-piperidone (6.57 g. 1 equiv.) in45 mL of THF was slowly added, at low temperature. The cooling bath wasremoved, and the mixture allowed to stir, at room temperature, for 12 h.5N hydrochloric acid (60 mL) was added, and the aqueous and organiclayers were separated. The organic layer was washed again with 1Nhydrochloric acid, the aqueous layers were combined and treated withsaturated aqueous ammonium hydroxide solution, and extracted intochloroform. The organic layer was washed with brine, and dried oversodium sulfate. The mixture was concentrated and purified by silica gelcolumn chromatography (2-5% methanol in dichloromethane eluent gradient)to provide the N-methyl-3-keto derivative of the title compound, whichwas dissolved in 70 mL of anhydrous tetrahydrofuran, cooled to 0° C.,and treated with 2.5 equivalents of borane (1M solution in THF). Themixture was allowed to warm to room temperature, and was then heated atreflux for 12 hours. The mixture was cooled to 0° C., 5N hydrochloricacid (14 mL) was added to the cooled mixture, and heating at reflux wasthen continued for an additional 5 hours. The mixture was cooled,concentrated, and partitioned between water and diethyl ether. Theorganic phase was separated, and the aqueous phase was treated withconcentrated ammonium hydroxide solution, and extracted with ether. Thecombined organic layer was washed with brine, dried over sodium sulfateand purified by silica gel column chromatography (2% methanol indichloromethane eluent) to give the N-methylated derivative of the titlecompound, which was dissolved in 1,2-dichloroethane, cooled to 0° C.,and treated with excess 1-chloroethylchloroformate, allowed to warm toroom temperature, and then heated at reflux for 12 hours. To the mixturewas added methanol (50 mL) and heating was continued for 3.5 additionalhours, after which time the mixture was cooled to room temperature,diluted with water, treated with saturated acqueous ammonium hydroxidesolution, and extracted into chloroform. The organic layer wasseparated, washed with brine, dried over sodium sulfate, concentrated,and purified by silica gel column chromatography (2% methanol indichloromethane) to give 2.25 g (19% yield over three steps) of thetitle compound as a waxy solid. FDMS (m/e=219).

Preparations 3-18

The following derivatives were prepared in similar fashion as inPreparations 1 and 2, by starting with the appropriately substitutedN,N-diethylbenzamide or naphthylamide derivative:

4-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 18% yield,FDMS (m/e=237).

6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 17% yield,FDMS (m/e=237).

benzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 30% yield,FDMS (m/e=253).

benzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidin]: 14% yield, FDMS(m/e=239).

benzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 60% yield,FDMS (m/e=253).

benzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]: 20% yield, FDMS(m/e=239).

6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 13% yield,FDMS (m/e=217).

6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]: 9% yield, FDMS(m/e=203).

5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 19% yield,FDMS (m/e=237).

5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]: 12% yield, FDMS(m/e=223).

6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 19% yield,FDMS (m/e=233).

6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]: 15% yield, FDMS(m/e=219).

5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]: 31% yield, FDMS(m/e=219). 4-fluorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one:23% yield, FDMS (m/e=221).4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 30% yield,FDMS (m/e=309).

6-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one: 10% yield,FDMS (m/e=309).

EXAMPLE 1 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[1-benzyl]piperidinylamino)-2-propanol

A solution of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (400 mg, 2.1 mmol)and 4-amino-1-benzylpiperidine (443 mg, 2.1 mmol) in 10 mL of methanolwas heated at reflux for 18 h. The solution was cooled, concentrated andpurified by silica gel chromatography (dichloromethane--5% methanol indichloromethane solvent gradient) to give 618 mg (78%) of the titlecompound as an amorphous solid. FDMS m/e=379 (M⁺ of free base). α[D]₅₈₉=-8.90 (c=0.52, chloroform).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              72.79     72.69                                                H              7.70      7.42                                                 N              11.07     11.02                                                ______________________________________                                    

EXAMPLE 2 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-(12-azadispiro[4.1.4.2]tridecan-13-one)amino)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-amino-12-azadispiro[4.1.4.2]tridecan-13-one. The resulting free basewas dissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 68% overall yield. mp 115°-117°. FDMSm/e=397 (M⁺ of free base). α[D]₅₈₉ =-5.11 (c=1.02, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.59     61.44                                                H              6.82      7.04                                                 N              8.62      8.45                                                 ______________________________________                                         ##STR32##

EXAMPLE 3 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[2,2,6,6-tetramethyl]piperidinylamino)-2-propanol

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-amino-2,2,6,6-tetramethylpiperidine in 68% yield. FDMS m/e=345 (M⁺ offree base). α[D]₅₈₉ =-2.54 (c=0.9, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.53     69.77                                                H               9.04      9.17                                                N              12.16     12.28                                                ______________________________________                                    

EXAMPLE 4 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propylamino)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and3-(10,11-dihydro-5H)-dibenz[b,f]azepin-5-yl-propanamine in 53% overallyield. FDMS m/e=441 (M⁺ of free base). α[D]₅₈₉ =-19.48 (c=0.62,methanol).

EXAMPLE 5 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(2-tetrahydrofurfurylamino)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 2-tetrahydrofurfurylamine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 49% overallyield. mp 112°-114°. FDMS m/e=290 (M⁺ of free base). α[D]₅₈₉ =-12.79(c=1.0, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              56.84     56.59                                                H              6.36      6.39                                                 N              7.36      7.66                                                 ______________________________________                                    

EXAMPLE 6 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3-[N-morpholino]propylamino)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3-(N-morpholino)propylamine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 33% overallyield. mp 120°-121°. FDMS m/e=333 (M⁺ of free base). α[D]₅₈₉ =-20.8(c=0.6, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              56.73     56.87                                                H              6.90      6.96                                                 N              9.92      9.77                                                 ______________________________________                                    

EXAMPLE 7 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(formyl)piperazin-1-yl)-2-propanol

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-formylpiperazine in 86%yield. mp 106°-107°. FDMS m/e=303 (M⁺ of free base). α[D]₅₈₉ =-1.98(c=1.0, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.35     62.13                                                H              6.98      7.11                                                 N              13.85     13.75                                                ______________________________________                                    

EXAMPLE 8 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2-pyridyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2-pyridyl)piperazine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 90% overallyield. FDMS m/e=352 (M⁺ of free base). α[D]₅₈₉ =-31.14 (c=0.86,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.72     59.43                                                H              5.92      6.13                                                 N              12.66     12.79                                                ______________________________________                                    

EXAMPLE 9 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazine. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMSm/e=423 (M⁺ of free base). α[D]₅₈₉ =-10.21 (c=0.82, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.81     60.59                                                H              6.08      6.19                                                 N              8.18      7.79                                                 ______________________________________                                    

EXAMPLE 10 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(2,6-dimethylphenyl)piperazine. The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 50% overall yield. FDMS m/e=379 (M⁺ of free base).α[D]₅₈₉ =-11.89 (c=0.47, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.95     63.93                                                H              6.65      6.36                                                 N              8.95      8.64                                                 ______________________________________                                    

EXAMPLE 11 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2,3-dimethylphenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(2,3-dimethylphenyl)piperazine. The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 83% overall yield. FDMS m/e=379 (M⁺ of free base).α[D]₅₈₉ =-9.84 (c=0.75, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.95     63.60                                                H              6.65      6.72                                                 N              8.95      8.91                                                 ______________________________________                                    

EXAMPLE 12 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-bis(4-fluorophenyl)methylenepiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(bis(4-fluorophenyl)methylenepiperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 88% overall yield. FDMS m/e=474 (M⁺ offree base). α[D]₅₈₉ =-8.49 (c=0.71, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.95     65.75                                                H              5.36      5.55                                                 N              4.96      4.61                                                 ______________________________________                                    

EXAMPLE 13

Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-quinolinyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-quinolinyl)piperazine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 64% overallyield. mp 150°-151°. FDMS m/e=402 (M⁺ of free base). α[D]₅₈₉ =-12.41(c=0.76, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.40     63.10                                                H              5.73      5.50                                                 N              11.37     11.25                                                ______________________________________                                    

EXAMPLE 14 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-bis(4-chlorophenyl)methylpiperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(bis(4-chlorophenyl)methylpiperazine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 82% overall yield. mp 123°-124°. FDMSm/e=510 (M⁺ of free base). α[D]₅₈₉ =-8.46 (c=0.89, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.00     59.72                                                H              5.20      5.50                                                 N              6.98      6.68                                                 ______________________________________                                    

EXAMPLE 15 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-trifluoromethylphenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(4-trifluoromethylphenyl)piperazine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=419 (M⁺ offree base). α[D]₅₈₉ =-7.78 (c=0.72, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              56.58     56.51                                                H              5.14      5.44                                                 N              8.25      7.96                                                 ______________________________________                                    

EXAMPLE 16 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2-trifluoromethylphenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(2-trifluoromethylphenyl)piperazine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 70% overall yield. mp 123°-124°. FDMSm/e=419 (M⁺ of free base). α[D]₅₈₉ =-7.01 (c=0.66, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              56.58     56.82                                                H              5.14      5.32                                                 N              8.25      8.05                                                 ______________________________________                                    

EXAMPLE 17 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3-bromophenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3-bromophenyl)piperazine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 84% overallyield. mp 144°-145°. FDMS m/e=429 (M⁺ of free base). α[D]₅₈₉ =-8.12(c=0.81, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              53.09     53.07                                                H              5.04      5.29                                                 N              8.07      7.99                                                 ______________________________________                                    

EXAMPLE 18 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(t-butyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-t-butyl)piperazine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 75% overallyield. mp 179°-180°. FDMS m/e=331 (M⁺ of free base). α[D]₅₈₉ =-4.73(c=0.93, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.84     59.70                                                H              7.41      7.17                                                 N              9.97      9.74                                                 ______________________________________                                    

EXAMPLE 19 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(3,4-dichlorophenyl)piperazine. The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 87% overall yield. FDMS m/e=419 (M⁺ of free base).α[D]₅₈₉ =-7.76 (c=0.82, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              54.13     54.43                                                H              4.94      5.03                                                 N              8.23      8.32                                                 ______________________________________                                    

EXAMPLE 20 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(isopropyl)piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-isopropyl)piperazine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 65% overallyield. mp 150°-152°. FDMS m/e=317 (M⁺ of free base). α[D]₅₈₉ =-6.63(c=0.99, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.96     58.68                                                H              7.17      6.87                                                 N              10.31     10.07                                                ______________________________________                                    

EXAMPLE 21 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-phenylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 80% overallyield. FDMS m/e=351 (M⁺ of free base). α[D]₅₈₉ =-15.49 (c=0.86,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.44     65.48                                                H              6.41      6.44                                                 N              6.36      6.06                                                 ______________________________________                                    

EXAMPLE 22 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3-phenylpropyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 73% overallyield. FDMS m/e=392 (M⁺ of free base). α[D]₅₈₉ =-13.53 (c=0.58,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.20     67.50                                                H              7.10      7.14                                                 N              5.80      5.62                                                 ______________________________________                                    

EXAMPLE 23 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-([4-(pyridazin-3-one-6-yl)phenyl]piperidin-1-yl)-2-propanol

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-[4-(pyridazin-3-one-6-yl)phenyl]piperidine in 72% yield. mp 202°-203°.FDMS m/e=446 (M⁺ of free base). α[D]₅₈₉ =-9.94 (c=0.84, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.93     69.84                                                H              6.77      6.92                                                 N              12.55     12.80                                                ______________________________________                                    

EXAMPLE 24 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(3-trifluoromethylphenyl)piperidine. The resulting free basewas dissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 59% overall yield. FDMS m/e=426 (M⁺ offree base). α[D]₅₈₉ =-11.39 (c=0.56, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              57.25     57.11                                                H              5.19      4.98                                                 N              5.34      5.14                                                 ______________________________________                                    

EXAMPLE 25 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4,4-diphenylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4,4-diphenylpiperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 60% overallyield. mp 198°-199°. FDMS m/e=426 (M⁺ of free base). α[D]₅₈₉ =-17.80(c=0.66, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.75     69.83                                                H              6.24      6.29                                                 N              5.42      5.08                                                 ______________________________________                                    

EXAMPLE 26 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 89% overallyield. FDMS m/e=466 (M⁺ of free base). α[D]₅₈₉ =-10.02 (c=0.72,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.20     71.03                                                H              6.52      6.84                                                 N              5.03      4.72                                                 ______________________________________                                    

EXAMPLE 27 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3-(1,2,4-triazolo[3,4-b]benzothiazolyl))piperazin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1-(3-(1,2,4-triazolo[3,4-b]benzothiazolyl))piperazine. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 56% overall yield. FDMSm/e=448 (M⁺ of free base). α[D]₅₈₉ =-10.42 (c=0.50, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              55.75     55.72                                                H              4.87      4.98                                                 N              15.60     15.43                                                ______________________________________                                         ##STR33##

EXAMPLE 28 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(diphenylmethyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(diphenylmethyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 81% overallyield. mp 160°-161°. FDMS m/e=441 (M⁺ of free base). α[D]₅₈₉ =-8.71(c=0.89, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.17     69.98                                                H              6.46      6.75                                                 N              5.28      4.93                                                 ______________________________________                                    

EXAMPLE 29 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(4-fluorophenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=384 (M⁺ offree base). α[D]₅₈₉ =-11.40 (c=0.66, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.75     60.46                                                H              5.74      5.79                                                 N              5.90      5.64                                                 ______________________________________                                    

EXAMPLE 30 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methoxyphenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 66% overallyield. FDMS m/e=380 (M⁺ of free base). α[D]₅₈₉ =-11.77 (c=0.61,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.82     63.61                                                H              6.43      6.65                                                 N              5.95      5.67                                                 ______________________________________                                    

EXAMPLE 31 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-trifluoromethylphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(3-trifluoromethylphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 50% overall yield. FDMS m/e=419 (M⁺ offree base). α[D]₅₈₉ =-11.62 (c=0.45, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.05     59.15                                                H              5.35      5.50                                                 N              5.51      5.26                                                 ______________________________________                                    

EXAMPLE 32 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-bis(4-fluorophenyl)methylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(bis(4-fluorophenyl)methylpiperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 64% overall yield. FDMS m/e=476 (M⁺ offree base). α[D]₅₈₉ =-9.85 (c=0.89, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.71     65.46                                                H              5.69      5.95                                                 N              4.94      4.74                                                 ______________________________________                                    

EXAMPLE 33 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-phenylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion fromS)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 69% overallyield. FDMS m/e=366 (M⁺ of free base). α[D]₅₈₉ =-10.45 (c=0.61,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.15     62.81                                                H              6.18      6.08                                                 N              6.14      5.99                                                 ______________________________________                                    

EXAMPLE 34 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(3-methoxyphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=396 (M⁺ offree base). α[D]₅₈₉ =-8.13 (c=0.69, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.73     61.51                                                H              6.21      6.18                                                 N              5.76      5.59                                                 ______________________________________                                    

EXAMPLE 35 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-piperidin-1-yl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(piperidin-1-yl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 60% overallyield. mp 220°-221°. FDMS m/e=358 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.73     61.33                                                H              7.43      7.06                                                 N              9.39      8.96                                                 ______________________________________                                    

EXAMPLE 36 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[benzodihydrofuran-3-one-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[benzodihydrofuran-3-one-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 73% overall yield. mp198°-199°. FDMS m/e=392 (M⁺ of free base). α[D]₅₈₉ =-12.04 (c=0.85,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.23     62.10                                                H              5.43      5.39                                                 N              5.81      5.93                                                 ______________________________________                                         ##STR34##

EXAMPLE 37 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting free basewas dissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=378 (M⁺ offree base). α[D]₅₈₉ =-10.28 (c=0.45, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.09     63.92                                                H              6.02      6.26                                                 N              5.98      5.93                                                 ______________________________________                                    

EXAMPLE 38 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-phenoxypiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(phenoxy)piperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 69% overallyield. FDMS m/e=366 (M⁺ of free base). α[D]₅₈₉ =-14.29 (c=0.5,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.15     63.89                                                H              6.18      6.08                                                 N              6.14      5.94                                                 ______________________________________                                    

EXAMPLE 39 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[1-(2-phenyl)benzimidazolyl]piperidinyl-1)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(1-(2-phenyl)benzimidazolyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 71% overall yield. mp 168°-170°. FDMSm/e=466 (M⁺ of free base). α[D]₅₈₉ =-8.44 (c=0.59, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.89     66.51                                                H              5.80      5.87                                                 N              10.07     9.77                                                 ______________________________________                                    

EXAMPLE 40 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[5-chloro-1-indol-2-one]piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(5-chloro-1-indol-2-one)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 59% overall yield. mp 230°-231°. FDMSm/e=439 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.93     59.13                                                H              5.33      5.41                                                 N              7.93      8.10                                                 ______________________________________                                    

EXAMPLE 41 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[2-(1-methyl)benzimidazolyl]piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(2-(1-methyl)benzimidazolyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 70% overall yield. FDMS m/e=404 (M⁺ offree base). α[D]₅₈₉ =-6.04 (c=0.53, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.15     63.09                                                H              6.11      6.47                                                 N              11.33     11.43                                                ______________________________________                                    

EXAMPLE 42 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-phenyl-4-(4-trifluoromethylphenoxy)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-phenyl-4-(4-trifluoromethylphenoxy)piperidine. The resulting free basewas dissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 49% overall yield. FDMS m/e=510 (M⁺ offree base). α[D]₅₈₉ =-11.99 (c=0.42, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.00     61.82                                                H              5.20      5.43                                                 N              4.66      4.58                                                 ______________________________________                                    

EXAMPLE 43 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1-heptamethyleneimino)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and heptamethyleneimine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 62% overallyield. FDMS m/e=302 (M⁺ of free base). α[D]₅₈₉ =-13.48 (c=0.61,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.21     60.98                                                H              7.19      7.35                                                 N              7.14      6.89                                                 ______________________________________                                    

EXAMPLE 44 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1-azabicyclo[3.2.2]nonanyl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-azabicyclo[3.2.2]nonane. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 85% overallyield. FDMS m/e=314 (M⁺ of free base). α[D]₅₈₉ =-20.39 (c=0.48,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.36     62.09                                                H              6.98      6.94                                                 N              6.93      6.59                                                 ______________________________________                                    

EXAMPLE 45 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(4-chlorophenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=401 (M⁺ offree base). α[D]₅₈₉ =-14.17 (c=0.45, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.72     59.06                                                H              5.54      5.66                                                 N              5.71      5.54                                                 ______________________________________                                    

EXAMPLE 46 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-[1-benzimidazol-2-one]piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(1-benzimidazol-2-one)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 88% overall yield. mp 123°-125°. FDMSm/e=406 (M⁺ of free base). α[D]₅₈₉ =-17.22 (c=0.48, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.48     60.38                                                H              5.68      5.86                                                 N              11.28     11.32                                                ______________________________________                                    

EXAMPLE 47 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-cyano-4-phenylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-cyano-4-phenylpiperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 57% overallyield. FDMS m/e=(M⁺ of free base). α[D]₅₈₉ =-12.76 (c=0.48, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.51     64.37                                                H              5.85      6.00                                                 N              9.03      8.71                                                 ______________________________________                                    

EXAMPLE 48 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(4-bromophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(4-bromophenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=444, 446 (M⁺of free base). α[D]₅₈₉ =-7.52 (c=0.45, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.33     59.54                                                H              5.66      5.56                                                 N              6.29      5.98                                                 ______________________________________                                    

EXAMPLE 49 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMSm/e=469 (M⁺ of free base). α[D]₅₈₉ =-11.53 (c=0.54, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              53.72     53.53                                                H              4.69      5.01                                                 N              5.01      4.83                                                 ______________________________________                                    

EXAMPLE 50 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-spiro[9H-fluorene-9,4']hexamethyleneimino-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-spiro[9H-fluorene-9,4']hexamethyleneimine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 64% overall yield. FDMS m/e=438 (M⁺ offree base). mp 131°-133°. α[D]₅₈₉ =-10.78 (c=0.43, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.44     70.38                                                H              6.10      6.34                                                 N              5.30      4.91                                                 ______________________________________                                         ##STR35##

EXAMPLE 51 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(trans-4-(3-hydroxyphenyl)-3-methyl-4-propylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andtrans-4-(3-hydroxyphenyl)-3-methyl-4-propylpiperidine. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 79% overall yield. mp116°-118°. FDMS m/e=422 (M⁺ of free base). α[D]₅₈₉ =-9.85 (c=1.02,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.61     65.77                                                H              7.08      7.09                                                 N              5.46      5.17                                                 ______________________________________                                    

EXAMPLE 52 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3,3-diphenylpyrrolidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,3-diphenylpyrrolidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 68% overallyield. FDMS m/e=412 (M⁺ of free base). mp 193°-194°. α[D]₅₈₉ =-9.11(c=0.33, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.31     69.06                                                H              6.02      5.94                                                 N              5.57      5.43                                                 ______________________________________                                    

EXAMPLE 53 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4,4-diphenylhexamethyleneimino-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4,4-diphenylhexamethyleneimine. The resulting free base was dissolved inethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 60% overall yield. FDMS m/e=440 (M⁺ of free base). mp103°-104°. α[D]₅₈₉ =-9.11 (c=0.39, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.17     70.04                                                H              6.46      6.71                                                 N              5.28      4.93                                                 ______________________________________                                    

EXAMPLE 54 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-methylphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion fromS)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 78% overallyield. FDMS m/e=364 (M⁺ of free base). α[D]₅₈₉ =-11.77 (c=0.34,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.06     66.19                                                H              6.65      6.81                                                 N              6.16      5.90                                                 ______________________________________                                    

EXAMPLE 55 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=336 (M⁺ offree base). α[D]₅₈₉ =-14.17 (c=0.61, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.78     64.48                                                H              6.14      5.84                                                 N              6.57      6.64                                                 ______________________________________                                    

EXAMPLE 56 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 48% overall yield. FDMSm/e=396 (M⁺ of free base). α[D]₅₈₉ =-9.34 (c=0.47, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.72     61.76                                                H              6.21      6.60                                                 N              5.76      5.91                                                 ______________________________________                                    

EXAMPLE 57 Preparation of (2S)-(-)-1-(4-indolyloxy-3-(6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMSm/e=405 (M⁺ of free base). α[D]₅₈₉ =-6.87 (c=0.44, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              55.77     55.70                                                H              4.88      5.14                                                 N              5.65      5.69                                                 ______________________________________                                    

EXAMPLE 58 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2-fluorophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-fluorophenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 40% overallyield. FDMS m/e=368 (M⁺ of free base). α[D]₅₈₉ =-12.31 (c=0.61,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.87     62.93                                                H              5.94      6.13                                                 N              6.11      5.96                                                 ______________________________________                                    

EXAMPLE 59 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2-methoxyphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-methoxyphenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 37% overallyield. FDMS m/e=380 (M⁺ of free base). α[D]₅₈₉ =-14.83 (c=0.81,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.82     63.87                                                H              6.43      6.58                                                 N              5.95      5.53                                                 ______________________________________                                    

EXAMPLE 60 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(benzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andbenzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 87% overall yield. FDMSm/e=442 (M⁺ of free base). α[D]₅₈₉ =-2.92 (c=1.02, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.41     65.31                                                H              5.30      5.40                                                 N              5.26      5.03                                                 ______________________________________                                         ##STR36##

EXAMPLE 61 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 40% overallyield. mp 195°-197°. FDMS m/e=422 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.93     60.61                                                H              5.51      5.89                                                 N              5.47      5.71                                                 ______________________________________                                    

EXAMPLE 62 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-trifluoromethoxyphenyl)piperidin-1-yl-2-propanol ethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(4-trifluoromethoxyphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=434 (M⁺ offree base). α[D]₅₈₉ =-13.45 (c=1.04, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              57.25     56.99                                                H              5.19      5.43                                                 N              5.34      5.04                                                 ______________________________________                                    

EXAMPLE 63 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-methylenedioxy)phenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(3,4-methylenedioxyphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 71% overall yield FDMS m/e=394 (M⁺ offree base). α[D]₅₈₉ =-15.73 (c=1.02, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.98     61.65                                                H              5.82      5.89                                                 N              5.78      5.44                                                 ______________________________________                                    

EXAMPLE 64 Preparation of(2s)-(-)-1-(4-indolyloxy)-3-(4-(2-naphthyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-naphthyl)piperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 74% overallyield. mp. 171°-172°. FDMS m/e=400 (M⁺ of free base). α[D]₅₈₉ =-13.51(c=1.04, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.56     68.28                                                H              6.16      6.45                                                 N              5.71      5.51                                                 ______________________________________                                    

EXAMPLE 65 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-trifluoromethylphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(4-trifluoromethylphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 34% overall yield. FDMS m/e=419 (M⁺ offree base). α[D]₅₈₉ =-10.15 (c=0.47, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.05     59.04                                                H              5.35      5.32                                                 N              5.51      5.03                                                 ______________________________________                                    

EXAMPLE 66 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3,3-dimethylspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and3,3-dimethylspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 52% overall yield. FDMSm/e=406 (M⁺ of free base). α[D]₅₈₉ =-11.87 (c=0.72, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.31     65.28                                                H              6.50      6.58                                                 N              5.64      5.43                                                 ______________________________________                                    

EXAMPLE 67 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[benzodihydrothiophene-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[benzodihydrothiophene-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 70% overall yield. FDMSm/e=394 (M⁺ of free base). α[D]₅₈₉ =-10.86 (c=0.40, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.97     61.73                                                H              5.82      5.89                                                 N              5.78      5.51                                                 ______________________________________                                         ##STR37##

EXAMPLE 68 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(4-fluorophenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-fluorophenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 30% overallyield. FDMS m/e=369 (M⁺ of free base). α[D]₅₈₉ =-2.49 (c=0.24,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.87     62.61                                                H              5.94      5.73                                                 N              6.11      5.82                                                 ______________________________________                                    

EXAMPLE 69 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3-methoxyphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-methoxyphenyl)piperidine.The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 30% overallyield. mp 121°-123°. FDMS m/e=381 (M⁺ of free base). α[D]₅₈₉ =-12.69(c=0.53, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.82     63.59                                                H              6.43      6.51                                                 N              5.95      5.90                                                 ______________________________________                                    

EXAMPLE 70 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[indane-1,4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[indane-1,4'-piperidine].The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 76% overallyield. mp 110°-112°. FDMS m/e=376 (M⁺ of free base). α[D]₅₈₉ =-11.60(c=0.46, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.94     66.64                                                H              6.48      6.52                                                 N              6.00      6.05                                                 ______________________________________                                         ##STR38##

EXAMPLE 71 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[1H-indene-1,4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[1H-indene-1,4'-piperidine]. The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 80% overall yield. mp 119°-120°. FDMS m/e=374 (M⁺ offree base). α[D]₅₈₉ =-5.51 (c=0.47, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.23     66.91                                                H              6.08      6.11                                                 N              6.03      5.88                                                 ______________________________________                                         ##STR39##

EXAMPLE 72 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-spiro[9H-fluorene-9,4']-piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[9H-fluorene-9,4'-piperidine]. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 57% overall yield. mp 133°-134°. FDMSm/e=424 (M⁺ of free base α[D]₅₈₉ =-9.15 (c=0.50, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.02     69.85                                                H              5.88      6.08                                                 N              5.44      5.29                                                 ______________________________________                                    

EXAMPLE 73 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-dimethoxyphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(3,4-dimethoxyphenyl)piperidine. The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 82% overall yield. FDMS m/e=410 (M⁺ of free base).α[D]₅₈₉ =-11.84 (c=0.46, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.39     62.12                                                H              6.44      6.48                                                 N              5.60      5.37                                                 ______________________________________                                    

EXAMPLE 74 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-chlorospiro[benzodihydrofuran-1(3H),4 '-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMSm/e=412 (M⁺ of free base). α[D]₅₈₉ =-5.60 (c=0.36, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.70     59.62                                                H              5.41      5.19                                                 N              5.57      5.59                                                 ______________________________________                                    

EXAMPLE 75 Preparation of1-(4-indolyloxy)-3-(8-[1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one])-2-propanol

The title compound was prepared in similar fashion from4-(oxiranylmethoxy)-1H-indole and1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one in 47% yield. FDMS m/e=420.mp 213°-214°. ##STR40##

EXAMPLE 76 Preparation of1-(4-indolyloxy)-3-([2-(1-methyl-1H-pyrrol-2-yl)ethyl]amino)-2-propanol

The title compound was prepared in similar fashion from4-(oxiranylmethoxy)-1H-indole and 2-(1-methyl-1H-pyrrol-2-yl)ethylaminein 60% yield. FDMS m/e=313. mp 105°-106°.

EXAMPLE 77 Preparation of1-(4-indolyloxy)-3-(4-phenylmethylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from4-(oxiranylmethoxy)-1H-indole and 4-phenylmethylpiperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 52% overallyield. FDMS m/e=364 (M+ of free base). mp 105°-107°.

EXAMPLE 78 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 86% overall yield. FDMSm/e=408 (M⁺ of free base). α[D]₅₈₉ =-23.58 (c=0.51, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.64     62.81                                                H              6.07      6.31                                                 N              5.62      5.90                                                 ______________________________________                                    

EXAMPLE 79 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-ethylenedioxy)phenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-(3,4-ethylenedioxyphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 66% overall yield FDMS m/e=408 (M⁺ offree base). α[D]₅₈₉ =-9.39 (c=0.53, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.64     62.46                                                H              6.07      5.96                                                 N              5.62      5.39                                                 ______________________________________                                    

EXAMPLE 80 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-fluorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-fluorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 88% overall yield. mp222°-223°. FDMS m/e=410 (M⁺ of free base). α[D]₅₈₉ =-94.9 (c=0.52,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.52     62.35                                                H              5.25      5.29                                                 N              2.80      2.69                                                 ______________________________________                                    

EXAMPLE 81 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(benzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andbenzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMSm/e=428 (M⁺ of free base). α[D]₅₈₉ =-31.5 (c=0.54, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.17     67.42                                                H              5.83      6.04                                                 N              5.40      5.55                                                 ______________________________________                                    

EXAMPLE 82 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMSm/e=404 (M⁺ of free base). α[D]₅₈₉ =-15.81 (C =0.51, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.58     65.33                                                H              6.11      5.91                                                 N              5.66      5.37                                                 ______________________________________                                         ##STR41##

EXAMPLE 83 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3,4-dihydro-2-oxo-7-methoxyspiro[naphthalene-1(2H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and3,4-dihydro-2-oxo-7-methoxyspiro[naphthalene-1(2H),4'-piperidine]. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 55% overallyield. FDMS m/e=434 (M⁺ of free base). α[D]₅₈₉ =-5.55 (c=0.54,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.11     64.40                                                H              6.15      6.38                                                 N              5.34      5.29                                                 ______________________________________                                    

EXAMPLE 84 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 49% overall yield. mp222°-224°. FDMS m/e=426 (M⁺ of free base). α[D]₅₈₉ =-14.95 (c=0.54,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.09     58.19                                                H              4.87      4.97                                                 N              5.42      5.53                                                 ______________________________________                                    

EXAMPLE 85 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 45% overall yield. mp147°-148°. FDMS m/e=426 (M⁺ of free base). α[D]₅₈₉ =-9.74 (c=0.72,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.09     58.31                                                H              4.87      4.73                                                 N              5.42      5.79                                                 ______________________________________                                    

EXAMPLE 86 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(benzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanol

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andbenzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one in yield. mp170°-172°. FDMS m/e=442 (M⁺ of free base). α[D]₅₈₉ =-38.1 (c=0.55,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              73.29     72.97                                                H              5.92      5.83                                                 N              6.33      6.05                                                 ______________________________________                                         ##STR42##

EXAMPLE 87 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1,5-dihydrospiro[4H-2-benzopyran-1,4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1,5-dihydrospiro[4H-2-benzopyran-1,4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 58% overall yield. FDMSm/e=392 (M⁺ of free base). [D]₅₈₉ =-23.56 (c=0.51, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     65.09                                                H              6.27      6.44                                                 N              5.81      6.14                                                 ______________________________________                                         ##STR43##

EXAMPLE 88 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 83% overallyield. mp 204°-205°. FDMS m/e=422 (M⁺ of free base). α[D]₅₈₉ =-8.62(c=0.58, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.93     61.13                                                H              5.51      5.55                                                 N              5.47      5.69                                                 ______________________________________                                    

EXAMPLE 89 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(benzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andbenzo[e]spiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMSm/e=428 (M⁺ of free base). α[D]₅₈₉ =-5.65 (c=0.53, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.17     66.99                                                H              5.83      5.92                                                 N              5.40      5.66                                                 ______________________________________                                    

EXAMPLE 90 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanol

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one, in 57%yield. mp 167°-168°. FDMS m/e=422 (M⁺ of free base). α[D]₅₈₉ =-97.0(c=0.78, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.23     68.52                                                H              6.20      6.36                                                 N              6.63      6.41                                                 ______________________________________                                    

EXAMPLE 91 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanol ethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 96% overall yield. mp227°-228°. FDMS m/e=406 (M⁺ of free base). α[D]₅₈₉ =-93.1 (c=0.57,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.90     62.66                                                H              5.68      5.80                                                 N              5.64      5.72                                                 ______________________________________                                    

EXAMPLE 92 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 59% overall yield. FDMSm/e=408 (M⁺ of free base). α[D]₅₈₉ =-7.07 (c=0.56, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.64     62.79                                                H              6.07      6.16                                                 N              5.62      5.83                                                 ______________________________________                                    

EXAMPLE 93 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-methylspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMSm/e=392 (M⁺ of free base). α[D]₅₈₉ =-21.47 (c=0.56, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     63.79                                                H              6.27      6.28                                                 N              5.81      5.59                                                 ______________________________________                                    

EXAMPLE 94 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 84% overall yield. FDMSm/e=408 (M⁺ of free base). α[D]₅₈₉ =-16.60 (c=0.54, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.64     62.38                                                H              6.07      5.91                                                 N              5.62      5.47                                                 ______________________________________                                    

EXAMPLE 95 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(spiro[3H-2-benzopyran-3,4'-piperidin]-1(4H)-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole andspiro[3H-2-benzopyran-3,4'-piperidin]-1(4H)-3-one. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 81% overall yield. FDMSm/e=406 (M⁺ of free base). α[D]₅₈₉ =-17.61 (c=0.51, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.90     62.65                                                H              5.68      5.44                                                 N              5.64      5.41                                                 ______________________________________                                         ##STR44##

EXAMPLE 96 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanol ethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 87% overall yield. mp222°-224° (decomp). FDMS m/e=426 (M⁺ of free base). α[D]₅₈₉ =-50.6(c=0.57, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.09     58.36                                                H              4.87      4.73                                                 N              5.42      5.57                                                 ______________________________________                                    

EXAMPLE 97 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMSm/e=412 (M⁺ of free base). α[D]₅₈₉ =-19.80 (c=0.50, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.70     59.53                                                H              5.41      5.42                                                 N              5.57      5.67                                                 ______________________________________                                    

EXAMPLE 98 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMSm/e=392 (M⁺ of free base). α[D]₅₈₉ =-12.34 (c=0.57, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     64.75                                                H              6.27      6.08                                                 N              5.81      5.82                                                 ______________________________________                                         ##STR45##

EXAMPLE 99 Preparation of1-(4-indolyloxy)-3-(spiro[3H-2-benzopyran-3,4'-piperidin]-1(4H)-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,spiro[3H-2-benzopyran-3,4'-piperidin]-1(4H)-3-one and 3 equivalents ofpotassium carbonate in acetonitrile was heated at reflux for 12 h. Themixture was cooled, diluted with ethyl acetate, and the organic layerwas separated and washed with brine. The crude residue was purified bysilica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 53% overall yield. FDMSm/e=390 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.99     65.28                                                H              5.87      5.95                                                 N              5.83      5.99                                                 ______________________________________                                    

EXAMPLE 100 Preparation of1-(4-indolyloxy)-3-(1-adamantylamino)-2-propanol hydrochloride

A mixture of 4-(oxiranylmethoxy)-1H-indole (0.946 g, 5 mmol) and1-adamantylamine (1.51 g, 10 mmol) in methanol (25 mL) was heated toreflux for 18 h. The methanol was evaporated and flash chromatography[silica gel, methylene chloride/methanol/ammonium hydroxide(100/10/0.5)] yielded 1.49 g solid. Crystallization as the hydrochloridesalt from ethyl acetate/methanol provided 1.47 g of colorless crystals(one mole of ethyl acetate bound to crystals). Mp 159°-161° C. Massspectrum, m⁺ =340. Anal (C₂₅ H₃₇ ClN₂ O₄) theory C, 64.57; H, 8.02; N,6.02; found C, 64.71; H, 7.88; N, 6.30.

EXAMPLE 101 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1-adamantylamino)-2-propanol hydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.89 g, 10 mmol) and1-adamantylamine (1.66 g, 11 mmol) in methanol (50 mL) was heated toreflux for 18 h. The methanol was evaporated and flash chromatography[silica gel, methylene chloride/methanol/ammonium hydroxide(100/10/0.5)] yielded 2.40 g solid. Crystallization as the hydrochloridesalt from ethyl acetate/methanol provided 1.68 g of colorless crystals(one mole of ethyl acetate bound to crystals). Mp 94° C. Mass spectrum,m⁺ =341. [α]²³ ₃₆₅ =-52.4° (C=0.01 g/mL, MeOH). Anal (C₂₅ H₃₇ ClN₂ O₄)theory C, 64.57; H, 8.02; N, 6.02; found C, 64.80; H, 8.04; N, 6.22.

EXAMPLE 102 Preparation of1-(4-indolyloxy)-3-(2-adamantylamino)-2-propanol hydrochloride

A mixture of 4-(oxiranylmethoxy)-1H-indole (0.927 g, 4.9 mmol) and2-adamantylamine (0.808 g, 5.3 mmol) in methanol (25 mL) was heated toreflux for 18 h. The methanol was evaporated and flash chromatography[silica gel, methylene chloride/methanol (85/15)] yielded 0.855 g oil.Crystallization as the hydrochloride salt from ethyl acetate/methanolprovided 0.62 g of colorless crystals. Mp>250° C. Mass spectrum, m⁺=340. Anal (C₂₁ H₂₉ ClN₂ O₂) theory C, 66.92; H, 7.75; N, 7.43; found C,66.92; H, 7.78; N, 7.27.

EXAMPLE 103 Preparation of(2R)-(+)-1-(4-indolyloxy)-3-(1-adamantylamino)-2-propanol hydrochloride

A mixture of (R)-(-)-4-(oxiranylmethoxy)-1H-indole (1.89 g, 10 mmol) and1-adamantylamine (1.66 g, 11 mmol) in methanol (50 mL) was heated toreflux for 18 h. The methanol was evaporated and flash chromatography[silica gel, methylene chloride/methanol/ammonium hydroxide(100/10/0.5)] yielded 2.54 g oil. Crystallization as the hydrochloridesalt from ethyl acetate/methanol provided 1.52 g of colorless crystals(one mole of ethyl acetate bound to crystals). Mp 95° C. Mass spectrum,m⁺ =340. [α]²³ ₃₆₅ =+46.1° (C=0.01 g/mL, MeOH). Anal (C₂₅ H₃₇ ClN₂ O₄)theory C, 64.57; H, 8.02; N, 6.02; found C, 64.65; H, 7.79; N, 6.25.

EXAMPLE 104 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(2-adamantylamino)-2-propanol hydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.89 g, 10 mmol) and2-adamantylamine (1.66 g, 11 mmol) in methanol (50 mL) was heated toreflux for 18 h. The methanol was evaporated to an oil andcrystallization as the hydrochloride salt from ethyl acetate/methanolprovided 1.45 g of colorless crystals Mp>250° C. Mass spectrum, m⁺ =340.[α]²³ ₃₆₅ =-48.8° (C=0.0032 g/mL, MeOH). Anal (C₂₁ H₂₉ ClN₂ O₂) theoryC, 66.92; H, 7.76; N, 7.43; found C, 66.64; H, 7.83; N, 7.61.

EXAMPLE 105 Preparation of1-(4-indolyloxy)-3-(1-adamantylmethylamino)-2-propanol hydrochloride

A mixture of 4-(oxiranylmethoxy)-1H-indole (0.568 g, 3 mmol) and1-adamantylmethylamine (0.545 g, 3.3 mmol) in methanol (25 mL) washeated to reflux for 18 h. The methanol was evaporated and flashchromatography [silica gel, methylene chloride/methanol (90/10)] yielded0.527 g oil. Crystallization as the hydrochloride salt from ethylacetate/methanol provided 0.277 g of colorless crystals Mp 228° C. Massspectrum, m⁺ =354. Anal (C₂₂ H₃₁ ClN₂ O₂) theory C, 67.59; H, 7.99; N,7.17; found C, 67.55; H, 8.16; N, 7.37.

EXAMPLE 106 Preparation of1-(4-indolyloxy)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-propanoldihydrochloride

A mixture of 4-(oxiranylmethoxy)-1H-indole (0.946 g, 5 mmol) and1-(2-methoxyphenyl)piperazine (1.05 g, 5.5 mmol) in methanol (30 mL) washeated to reflux for 18 h. The methanol was evaporated and flashchromatography [silica gel, methylene chloride/methanol (97/3)] yielded1.75 g oil. Crystallization as the dihydrochloride salt from ethylacetate/methanol provided 1.56 g of colorless crystals. Mp 108° C. Massspectrum, m⁺ =381. Exact mass, theory 382.2131; found 382.2157.

EXAMPLE 107 Preparation of(2R)-(+)-1-(4-indolyloxy)-3-(2-adamantylamino)-2-propanol hydrochloride

A mixture of (R)-(-)-4-(oxiranylmethoxy)-1H-indole (0.946 g, 5 mmol) and2-adamantylamine (0.80 g, 5.25 mmol) in methanol (30 mL) was heated toreflux for 18 h. The methanol was evaporated t o an oil andcrystallization as the hydrochloride sa it from ethanol provided 0.60 gof off-white crystals. Mp>250° C. Mass spectrum, m⁺ =340. [α]²³ ₃₆₅=+41.8° (C=0.01 g/mL, MeOH). Anal (C₂₁ H₂₉ ClN₂ O₂) theory C, 66.92; H,7.75; N, 7.43; found C, 66.97; H, 7.89; N, 7.42.

EXAMPLE 108 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-propanoldihydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.89 g, 10 mmol) and1-(2-methoxyphenyl)piperazine (2.11 g, 11 mmol) in methanol (75 mL) washeated to reflux for 18 h. The methanol was evaporated and flashchromatography (silica gel, ethyl acetate) yielded 3.52 g oil.Crystallization as the dihydrochloride salt in ethyl acetate provided3.84 g of colorless crystals Mp 176° C. Mass spectrum, m⁺ =382. [α]²³₃₆₅ =-37.1° (C=0.01 g/mL, MeOH). Anal (C₂₂ H₂₉ Cl₂ N₃ O₃) theory C,58.15; H, 6.43; N, 9.25; found C, 58.44; H, 6.46; N, 9.17

EXAMPLE 109 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1-adamantylmethylamino)-2-propanolhydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.946 g, 5 mmol) and1-adamantylmethylamine (0.91 g, 5.5 mmol) in methanol (30 mL) was heatedto reflux for 18 h. The methanol was evaporated and flash chromatography[silica gel, methylene chloride/methanol (90/10)] yielded 1.18 g oil.Crystallization as the hydrochloride salt from 2-propanol provided 0.711g crystals. Mp 118° C. Mass spectrum, m⁺ =354. [α]²³ ₃₆₅ =-41.3°(C=0.0075 g/mL, MeOH). Anal (C₂₂ H₃₁ ClN₂ O₂) theory C, 67.59; H, 7.99;N, 7.16; found C, 67.68; H, 8.09; N, 6.95.

EXAMPLE 110 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-(2-pyrimidinyl)-1-piperazinyl]-2-propanoldihydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.65 g, 8.7 mmol)and 1-(2-pyrimidinyl)piperazine (1.58 g, 9.6 mmol) in methanol (75 mL)was heated to reflux for 18 h. The methanol was evaporated and flashchromatography [silica gel, ethyl acetate/ethanol (95/5)] yielded 2.81 goil. Crystallization as the dihydrochloride salt from methanol provided0.767 g of light yellow crystals. Mp 240° C. Mass spectrum m⁺ =353 [α]²³₅₈₉ =-16.8° (C=0.01 g/mL MeOH). Anal (C₁₉ H₂₅ Cl₂ N₅ O₂) theory C,53.53; H, 5.91; N, 16.43; found C, 53.46; H, 5.94; N, 16.49.

EXAMPLE 111 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-(1-naphthyl)-1-piperazinyl]-2-propanolhydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.72 g, 9.1 mmol)and 1-(1-naphthyl)piperazine [see J. Med. Chem. 29, 2375 (1986)] (2.12g, 10 mmol) in methanol (75 mL) was heated to reflux for 18 h. Themethanol was evaporated and flash chromatography (silica gel, ethylacetate) yielded 1.86 g oil. Crystallization as the hydrochloride saltfrom methanol/diethyl ether provided 1.32 g of colorless crystals. Mp140° C. Mass spectrum, m⁺ =401. [α]²³ ₃₆₅ =-41.9° (C=0.0077 g/mL, MeOH).Anal (C₂₅ H₂₈ ClN₃ O₂) theory C, 68.56; H, 6.44; N, 9.59; found C,68.46; H, 6.59; N, 9.58.

EXAMPLE 112 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(3,5,7-trimethyl-1-adamantylamino)-2-propanolhydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.511 g, 2.7 mmol)and 3,5,7-trimethyl-1-adamantylamine (0.587 g, 3 mmol) in methanol (15mL) was heated to reflux for 18 h. The methanol was evaporated and flashchromatography [silica gel, methylene chloride/methanol/ammoniumhydroxide (100/5/0.5)] yielded 0.722 g solid foam. Crystallization asthe hydrochloride salt in ethyl acetate provided 0.728 g of colorlesscrystals. Mp>250° C. Mass spectrum, m⁺ =382. [α]²³ ₃₆₅ =-63.7° (C=0.0076g/mL MeOH). Anal (C₂₄ H₃₅ ClN₂ O₂) theory C, 68.80; H, 8.42; N, 6.69;found C, 68.60; H, 8.63; N, 6.60.

EXAMPLE 113 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(1-methyl-1-adamantylamino)-2-propanolhydrochloride

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.511 g, 2.7 mmol)and 1-methyl-1-adamantylamine (see Org. Syn., Coll. Vol. 7, 433) (0.486g, 2.9 mmol) in methanol (15 mL) was heated to reflux for 18 h. Themethanol was evaporated and flash chromatography [silica gel, methylenechloride/methanol/ammonium hydroxide (100/3/0.5)] yielded 0.787 g oil.Crystallization as the hydrochloride salt from acetonitrile provided0.623 g of colorless crystals. Mp 241° C. Mass spectrum, m⁺ =355. [α]²³₅₈₉ =-16.6° (C=0.0073 g/mL, MeOH). Anal (C₂₂ H₃₁ ClN₂ O₂) theory C,67.58; H, 7.99; N, 7.17; found C, 67.35; H, 8.18; N, 7.15.

EXAMPLE 114 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]-2-propanoldihydrochloride monohydrate

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.946 g, 5 mmol) and1-(5-methoxy-4-pyrimidinyl)piperazine (see European Patent App.92121519.0) (1.07 g, 5.5 mmol) in methanol (30 mL) was heated to refluxfor 18 h. The methanol was evaporated and flash chromatography [silicagel, methylene chloride/methanol (93/7)] yielded 0.873 g oil.Crystallization as the dihydrochloride monohydrate salt from methanolprovided 0.625 g of colorless crystals Mp 222° C. Mass spectrum, m⁺=383. [α]²³ ₅₈₉ =-27.2° (C=0.0076 g/mL, MeOH). Anal (C₂₀ H₂₉ Cl₂ N₅ O₄)theory C, 50.64; H, 6.16; N, 14.76; found C, 50.77; H, 6.08; N, 14.53.

EXAMPLE 115 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(8-[1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one])-2-propanol,maleate

A mixture of (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.8 g, 9.5 mmol) and1-phenyl-1,3,8-triazospiro[4,5]decan-4-one (2.2 g, 9.5 mmol) in methanol(25 mL) was heated to reflux for 18 h. The methanol was removed underreduced pressure. Preparative liquid chromatography [Waters Prep LC/500A, Prep PAK-500/silica gel cartridge, 8 L gradient, methylenechloride/methanol/ammonium hydroxide (95/5/0.5)] yielded 3.3 g (82.5%)of a white foam. Crystallization as the maleate salt from ethylacetate/methanol provided 0.7 g of pale yellow needles. mp 205°-206° C.mass spectrum (70 eV), m/e (relative intensity) 421 (M+1, 100); [α]_(D)²³ -9.2° (c=1, MeOH), [α]₃₆₅ ²³ -21.5° (C=1, MeOH). Anal (C₂₈ H₃₂ N₄ O₇)Theory C, 62.68; H, 6.01; N, 10.44; Found C, 62.40; H, 5.97; N, 10.70.

EXAMPLE 116 Preparation of(2R)-(+)-1-(4-indolyloxy)-3-(8-[1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one])-2-propanol,maleate

The title compound was prepared in the same manner as the Example above,in 73.8% yield. Crystallization as the maleate salt from ethylacetate/methanol provided 2.7 g of a white powder. mp 201°-202° C. massspectrum (70 eV), m/e (relative intensity) 421 (M+1, 100); [α]_(D) ²³+9.5° (C=1, MeOH), [α]₃₆₅ ²³ +25.4° (c=1, MeOH) Anal (C₂₈ H₃₂ N₄ O₇)Theory C, 62.68; H, 6.01; N, 10.44; Found C, 62.95; H, 6.30; N, 10.20.

Preparation 19 Preparation of1-(1H-indole-4-oxy)-3-tosylate)-2-methoxypropane

A solution of dimethyl 2-methoxymalonate 14.6 ml, 105 mmol) in drytetrahydrofuran (70 mL) was added dropwise to a 7° slurry of lithiumaluminum hydride (10.0 g, 262 mmol) in dry tetrahydrofuran (160 mL). Theresulting mixture was stirred 18 h at room temperature. The reactionmixture was cooled to 0° and the excess lithium aluminum hydride wasquenched by the dropwise addition of a saturated sodium sulfatesolution. Filtration and concentration of the filtrate provided 4.45 gof crude product. The filter cake was triturated with refluxingtetrahydrofuran for 18 h to provide an additional 4.2 g of crudeproduct. This material was combined with the product of a previousreaction to give 10.55 g of crude product. Distillation yielded 7.5 g(54.3%) of homogeneous product as a clear colorless oil. bp 109°-112° at4.5 torr. Anal (C₄ H₁₀ O₃) Theory C, 45.27; H, 9.50; Found C, 45.55; H,9.45.

A mixture of the above 1,3-dihydroxy-2-methoxypropane (7.24 g, 68.2mmol) and p-toluenesulfonyl chloride (29.9 g, 157 mmol) in pyridine (100mL) was stirred 5 h at 0° and let stand at 0° for 18 h. Productisolation (water/ice, ethyl acetate, cold 5N hydrochloric acid, water,brine, sodium sulfate) yielded 27.5 g (97.2%) of a pale yellow oil. Massspectrum (70 eV), m/e (relative intensity) 414 (M⁺, 100); Anal (C₁₈ H₂₂O₇ S₂) Theory C, 52.16; H, 5.35; Found C, 52.37; H, 5.42.

A solution of 4-hydroxyindole (6.94 g, 52.1 mmol) in drydimethylformamide (80 mL) was added dropwise to a slurry of sodiumhydride (2.2 g of a 60% dispersion in oil, 54.7 mmol) in drydimethylformamide (20 mL). The resulting mixture was stirred one hour atroom temperature. This mixture was added dropwise to a solution of theabove 1,3-ditosylate-2-methoxypropane (27 g, 65.1 mmol) indimethylformamide (155 mL) at 0°. The reaction was stirred at roomtemperature for 16 h. Product isolation (water, ether/ethyl acetate,water, brine, sodium sulfate) and flash chromatography (silica gel,methylene chloride) provided 17.9 g (91.3%) of product as a colorlessoil. Mass spectrum (70 eV), m/e (relative intensity) 375 (M⁺, 100).

EXAMPLE 117 Preparation of1-(4-indolyloxy)-3-(1-adamantylamino)-2-methoxypropane ethanedioate

A mixture of 1-(1H-indole-4-oxy)-3-(tosylate)-2-methoxypropane (4.5 g,11.9 mmol) and 1-adamantylamine (5.4 g, 35.7 mmol) in dimethylformamide(30 mL) was heated to 85° C. for 18 h. Product isolation (water, diethylether, water, brine, sodium sulfate) yielded 5.0 g of crude product.Preparative liquid chromatography [Waters Prep LC/500 A, PrepPAK-500/silica gel cartridge, 8 L gradient, methylenechloride/methanol/ammonium hydroxide (95/5/0.5)] yielded 2.28 g (54.0%)of a yellow foam. Crystallization as the oxalate salt from ethyl acetateprovided 2.54 g of an off white powder. mp 132°-134° C. mass spectrum(70 eV), m/e (relative intensity) 355 (M+1, 100). Anal (C₂₄ H₃₂ N₂ O₆)Theory C, 64.85; H, 7.26; N, 6.30; Found C, 64.82; H, 7.28; N, 6.23.

EXAMPLE 118 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(4-fluorobiphenyl)piperidin-1-yl)-2-propanolethanedioate

To a solution of(2S)-(-)-1-(1H-indole-4-oxy)-3-(4-hydroxy-4-(4-bromophenyl)piperidin-1-yl)-2-propanol(250 mg, 0.56 mmol) in 2 mL of toluene and 0.1 mL of methanol was addedtetrakis(triphenylphosphine) palladium (0) (0.02 equiv., 13 mg),4-fluorophenylboronic acid ((1.2 equiv., 94 mg), and 0.6 mL of 2M Na₂CO₃ solution, and the mixture was heated at 80° C. for 20 h. Thesolution was cooled, diluted with a solution ofdichloromethane/methanol/aqueous ammonium hydroxide (100:10:1) and theorganic phase was separated and washed with 2M Na₂ CO₃ and brine, anddried over sodium sulfate. The resulting oil was purified by silica gelchromatography (dichloromethane-5% methanol in dichloromethane gradient)to give the free base as a white foam which was dissolved in ethylacetate and precipitated with one equivalent of oxalic acid in ethylacetate, to give the title compound in 63% overall yield. mp. 123°-124°C. FDMS m/e=460 (M⁺ of free base). α[D]₅₈₉ =-8.89 (c=0.89, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.44     65.41                                                H              5.67      5.95                                                 N              5.09      4.73                                                 ______________________________________                                    

EXAMPLE 119 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(3-trifluoromethylbiphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared as described above, viapalladium-mediated coupling of(2S)-(-)-1-(1H-indole-4-oxy)-3-(4-hydroxy-4-(4-bromophenyl)piperidin-1-yl)-2-propanoland 3-trifluoromethylphenylboronic acid. The resulting free base wasdissolved in ethyl acetate and precipitated with one equivalent ofoxalic acid in ethyl acetate, to give the title compound in 58% overallyield. mp. 132°-134° C. FDMS m/e=510 (M⁺ of free base). α[D]₅₈₉ =-8.47(c=1.06, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.00     62.16                                                H              5.20      5.49                                                 N              4.66      4.49                                                 ______________________________________                                    

EXAMPLE 120 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-hydroxy-4-(4-methoxybiphenyl)piperidin-1-yl)-2-propanolethanedioate

The title compound was prepared as described previously, viapalladium-mediated coupling of(2S)-(-)-1-(1H-indole-4-oxy)-3-(4-hydroxy-4-(4-bromophenyl)piperidin-1-yl)-2-propanoland 4-methoxyphenylboronic acid. The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 39% overall yield. mp.175°-176° C. FDMS m/e=472 (M⁺ of free base). α[D]₅₈₉ =-4.84 (c=1.03,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.18     66.34                                                H              6.09      5.95                                                 N              4.98      4.79                                                 ______________________________________                                    

EXAMPLE 121 Preparation of1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 74% overall yield. mp210°-211°. FDMS m/e=406 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.90     62.92                                                H              5.68      5.70                                                 N              5.64      5.56                                                 ______________________________________                                    

EXAMPLE 122 Preparation of1-(4-indolyloxy)-3-(6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 28% overall yield. FDMSm/e=410 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.94     60.06                                                H              5.03      5.19                                                 N              5.59      5.76                                                 ______________________________________                                    

EXAMPLE 123 Preparation of1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,5-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 62% overall yield. mp 181°(decomp.) FDMS m/e=392 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     64.42                                                H              6.27      6.35                                                 N              5.81      5.62                                                 ______________________________________                                    

EXAMPLE 124 Preparation of1-(4-indolyloxy)-3-(6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-1-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-chlorospiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 50% overall yield. FDMSm/e=396 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.66     61.67                                                H              5.59      5.67                                                 N              5.75      5.72                                                 ______________________________________                                    

EXAMPLE 125 Preparation of1-(4-indolyloxy)-3-(3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidine] and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 37% overall yield. FDMSm/e=388 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.77     67.58                                                H              6.32      6.49                                                 N              5.85      5.89                                                 ______________________________________                                    

EXAMPLE 126 Preparation of1-(4-indolyloxy)-3-(4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of1-chloro-3-(1H-indole-4-oxy)propane,4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]and 3 equivalents of potassium carbonate in acetonitrile was heated atreflux for 12 h. The mixture was cooled, diluted with ethyl acetate, andthe organic layer was separated and washed with brine. The crude residuewas purified by silica gel chromatography (dichloromethane/5% methanolin dichloromethane gradient eluent). The resulting free base wasdissolved in ethyl acetate and precipitated with one equivalent ofoxalic acid in ethyl acetate, to give the title compound in 54% overallyield. FDMS m/e=392 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     64.98                                                H              6.27      6.29                                                 N              5.81      5.62                                                 ______________________________________                                    

EXAMPLE 127 Preparation of1-(4-indolyloxy)-3-(6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 58% overall yield. FDMSm/e=392 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     65.00                                                H              6.27      6.34                                                 N              5.81      6.01                                                 ______________________________________                                    

EXAMPLE 128 Preparation of1-(4-indolyloxy)-3-(6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propane ethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 56% overall yield FDMSm/e=390 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.99     65.08                                                H              5.87      6.14                                                 N              5.83      6.06                                                 ______________________________________                                    

EXAMPLE 129 Preparation of1-(4-indolyloxy)-3-(6-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-methylspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 27% overall yield. FDMSm/e=376 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.94     67.15                                                H              6.48      6.64                                                 N              6.00      6.23                                                 ______________________________________                                    

EXAMPLE 130 Preparation of1-(4-indolyloxy)-3-(5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy propane,5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 46% overall yield. mp214°-217° (decomp.) FDMS m/e=410 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.94     60.12                                                H              5.03      5.12                                                 N              5.59      5.89                                                 ______________________________________                                    

EXAMPLE 131 Preparation of1-(4-indolyloxy)-3-(5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,5-chlorospiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 58% overall yield. mp200°-202°. FDMS m/e=396 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.66     61.66                                                H              5.59      5.70                                                 N              5.75      5.69                                                 ______________________________________                                    

EXAMPLE 132 Preparation of1-(4-indolyloxy)-3-(1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(4-indolyloxy)propane,1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidine] and 3 equivalents ofpotassium carbonate in acetonitrile was heated at reflux for 12 h. Themixture was cooled, diluted with ethyl acetate, and the organic layerwas separated and washed with brine. The crude residue was purified bysilica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 62% overall yield. FDMSm/e=376 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.94     66.14                                                H              6.48      6.44                                                 N              6.00      6.00                                                 ______________________________________                                    

EXAMPLE 133 Preparation of1-(4-indolyloxy)-3-(4-phenyl-1-piperidinyl)propane oxalate

A mixture of 1-(1H-indole-4-oxy)-3-chloropropane (0.420 g, 2 mmol),4-phenylpiperidine (0.322 g, 2 mmol), sodium carbonate (0.530 g, 5 mmol)and 10 mL dimethylformamide was heated at 100° C. for 18 h. Evaporationof dimethylformamide, dilution with methylene chloride, washing withwater and drying (sodium sulfate) yielded 0.759 g oil. Flashchromatography [silica gel, methylene chloride/methanol (93/7)] yielded0.509 g oil. Crystallization as the oxalate salt from ethanol provided0.297 g of light yellow crystals. Mp 137°-139° C. Mass spectrum, m⁺=334. Anal (C₂₄ H₂₈ N₂ O₅) theory C, 67.91; H, 6.65; N, 6.60; found C,68.00; H, 6.52; N, 6.76.

EXAMPLE 134 Preparation of1-(4-indolyloxy)-3-[4-(2-methoxyphenyl)-1-piperazinyl]propane oxalate

A mixture of 1-(1H-indole-4-oxy)-3-chloropropane (0.420 g, 2 mmol),1-(2-methoxyphenyl)piperazine (0.384 g, 2 mmol), sodium carbonate (0.530g, 5 mmol) and 10 mL dimethylformamide was heated at 100° C. for 18 h.Evaporation of dimethylformamide, dilution with methylene chloride,washing with water and drying (sodium sulfate) yielded 0.819 g oil.Flash chromatography [silica gel, methylene chloride/methanol (95/5)]yielded 0.629 g oil. Crystallization as the oxalate salt in ethylacetate provided 0.309 g of colorless crystals. Mp 100° C. Massspectrum, m⁺ =365. Anal (C₂₄ H₂₉ N₃ O₆) theory C, 63.28; H, 6.42; N,9.22; found C, 63.02; H, 6.33; N, 9.38.

EXAMPLE 135 Preparation of4-(1-adamantylamino)-1-(4-indolyloxy)-3-butanol hydrochloride

Diethyl azodicarboxylate (12.5 ml, 79.3 mmol) was added dropwise to a 5°C. solution of 4-hydroxy-1H-indole (10.56 g, 79.3 mmol),1,2-epoxy-4-butanol (6.99 g, 79.3 mmol) and triphenylphosphine (20.8 g,79.3 mmol) in dry tetrahydrofuran (150 mL). The resulting mixture wasstirred eighteen hours at room temperature. The tetrahydrofuran wasremoved under reduced pressure. The residue was diluted with diethylether and filtered to remove impurities. The diethyl ether was removedunder reduced pressure to give 54.1 g of a brown oil, which was purifiedby preparative liquid chromatography [Waters Prep LC/500 A, PrepPAK-500/silica gel cartridge, 8L gradient, methylenechloride/methanol/ammonium hydroxide (99/1/0.5) to (97/3/0.5)] to obtain3.5 g (21.7%) of a clear colorless oil. mass spectrum (70 eV), m/e(relative intensity) 203 (M⁺, 100).

A mixture of the 1,2-epoxy-4-(1H-indol-4-yloxy)butane (1.52 g, 7.5 mmol)prepared above and 1-adamantylamine (1.25 g, 8.2 mmol) in methanol (20mL) was heated to reflux for 18 h. The methanol was removed underreduced pressure to yield a white solid. Preparative liquidchromatography [Waters Prep LC/500 A, Prep PAK-500/silica gel cartridge,8L gradient, methylene chloride/methanol/ammonium hydroxide (95/5/0.5)]yielded 2.0 g (75.5%) of a white solid. Crystallization as thehydrochloride salt from ethyl acetate/methanol provided 1.46 g of an offwhite powder. mp 260°-2° C. mass spectrum (70 eV), m/e (relativeintensity) 354 (M⁺, 100). Anal (C₂₂ H₃₀ N₂ O₂.HCl) Theory C, 67.59; H,7.99; N, 7.17; Found C, 67.55; H, 7.76; N, 7.24.

EXAMPLE 136 Preparation of(S)-(-)-1-(4-indolyloxy)-3-(2-adamantyl-N-methylamino)-2-propanolsuccinate

A mixture of (S)-(+)-(4-oxiranylmethoxy)-1H-indole (0.910 g, 4.8 mmol)and 2-adamantyl-N-methylamine (0.872 g, 5.3 mmol) in methanol (30 mL)was heated to reflux for 3 h. The methanol was evaporated and flashchromatography [silica gel, methylene chloride/methanol (93/7)] yielded1.41 g oil. Crystallization as the succinate salt in ethyl acetateprovided 1.05 g of crystals. Mp 75°-78° C. Mass spectrum, m⁺ =354. [α]²³₅₈₉ =-13.2° (C=0.0089 g/mL, MeOH). Anal (C₂₆ H₃₆ N₂ O₆) theory C, 66.08;H, 7.68; N, 5.93; found C, 66.19; H, 7.80; N, 5.67.

EXAMPLE 137 Preparation of(S)-(+)-1-(4-indolyloxy)-1-phenyl-3-(4-phenylpiperidin-1-yl)propanehydrochloride

A mixture of (R)-3-chloro-1-phenyl-1-propanol (5.11 g, 30 mmol),4-hydroxy-1H-indole (4.0 g, 30 mmol) and triphenyl phosphine (7.86 g, 30mmol) were stirred together in tetrahydrofuran (90 mL) at ambienttemperature. Diethyl azodicarboxylate (4.72 mL, 30 mmol) was addedslowly. The resulting solution was stirred at ambient temperature for 18h. Evaporation of the tetrahydrofuran followed by flash chromatography[silica gel, hexanes/ethyl acetate (3/1)] yielded 3.07 g oil. Massspectrum, m⁺ =285.

The above (S)-1-(4-indolyloxy)-1-phenyl-3-chloropropane (0.572 g, 2mmol), 4-phenylpiperidine (0.322 g, 2 mmol) and sodium carbonate (0.53g, 5 mmol) were mixed together in 10 mL dimethylformamide. This mixturewas heated at 100° C. for 18 h. Evaporation of dimethylformamide,dilution with methylene chloride, washing with water and drying (sodiumsulfate) yielded 0.863 g oil. Flash chromatography [silica gel,methylene chloride/methanol (95/5)] yielded 0.277 g oil. Crystallizationas the hydrochloride salt in diethyl ether provided 0.195 g of colorlesssolid. Mp 130° C. Mass spectrum, m⁺ =410. [α]²³ ₅₈₉ =76.9° (C=0.009g/mL, MeOH). Anal (C₂₈ H₃₁ ClN₂ O) theory C, 75.23; H, 6.99; N, 6.27;found C, 74.96; H, 6.88; N, 6.48.

EXAMPLE 138 Preparation of1-(4-indolyloxy)-3-[4-(1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]propane

A mixture of 1-chloro-3-hydroxypropane (4.2mL, 50 mmol),4-hydroxy-1H-indole (6.66 g, 50 mmol) and triphenyl phosphine (13.1 g,50 mmol) were stirred together in tetrahydrofuran (150 mL) at ambienttemperature. Diethyl azodicarboxylate (7.9 ml, 50 mmol) was addedslowly. The resulting solution was stirred at ambient temperature 18 h.Evaporation of the tetrahydrofuran followed by dilution with diethylether (200 mL), filtration, washing resulting filtrate with a 2N sodiumhydroxide solution and brine, gave after drying (sodium sulfate) andevaporation 24.97 g oil. Flash chromatography [silica gel, hexanes/ethylacetate (3/1)] yielded 5.93 g oil which crystallized. Mass spectrum, m⁺=209.

The above 1-(4-indolyloxy)-3-chloropropane (0.629 g, 3 mmol),3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.595 g, 3 mmol) andsodium carbonate (0.795 g, 7.5 mmol) were mixed together in 15 mLdimethylformamide. This mixture was heated at 100° C. for 18 h.Evaporation of dimethylformamide, dilution with water andcrystallization of the resulting precipitate from ethanol provided 0.582g of yellow crystals. Mp 192°-194° C. Mass spectrum, m⁺ =371. Anal (C₂₄H₂₅ N₃ O) theory C, 77.60; H, 6.78; N, 11.31; found C, 77.49; H, 6.53;N, 11.29.

EXAMPLE 139 Preparation of1-(4-indolyloxy)-3-[4-(2-naphthyl)piperazin-1-yl]propane oxalate

1-(4-indolyloxy)-3-chloropropane (0.159 g, 0.75 mmol),1-(2-naphthyl)piperazine (0.161 g, 0.75 mmol) and sodium carbonate(0.201 g, 1.89 mmol) were mixed together in 7 mL dimethylformamide andheated at 100° C. for 18 h. Evaporation of dimethylformamide, dilutionwith water and extractions with ethyl acetate provided 0.303 g. of oil.Crystallization as the oxalate salt from methanol provided 0.083 g ofcolorless crystals. Mp 209° C. Mass spectrum, m⁺ =385. Anal (C₂₇ H₂₉ N₃O₅) theory C, 68.20; H, 6.15; N, 8.84; found C, 68.47; H, 6.33; N, 8.60.

EXAMPLE 140 Preparation of1-(4-indolyloxy)-3-[4-(1H-indol-3-yl)piperidin-1-yl]propanehydrochloride

The product of Example 138 (0.370 g, 1 mmol) was hydrogenated (Pd/C, 40°C./18 h) in ethanol. Filtration, evaporation and flash chromatography[silica gel, methylene chloride/methanol/ammonium hydroxide (100/3/0.5)]yielded 0.177 g oil. Crystallization as the hydrochloride salt indiethyl ether provided 0.154 g of colorless solid. Mass spectrum, m⁺=373. Anal (C₂₄ H₂₈ ClN₃ O) theory C, 70.31; H, 6.88; N, 10.25; found C,70.01; H, 6.91; N, 10.07.

EXAMPLE 141 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-propanolethanedioate

The title compound was prepared according to Example 1 from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-phenyl-1,2,3,6-tetrahydropyridine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 60% overall yield as a white foam. FDMSm/e=348 (M⁺ of free base). α[D]₅₈₉ =-17.09 (c=0.49, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.74     65.78                                                H              5.98      6.04                                                 N              6.39      6.07                                                 ______________________________________                                    

EXAMPLE 142 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-(2-hydroxyimino)ethyl-4-phenylpiperidin-1-yl)-2-propanolethanedioate

The title compound was prepared by treating a solution of(2S)-(-)-1-(4-indolyloxy)-3-(4-acetyl-4-phenylpiperidin-1-yl)-2-propanolwith excess hydroxylamine hydrochloride (5 equivalents) and 5 molar aq.sodium hydroxide solution in ethanol, with heating at reflux for onehour. The mixture was cooled, diluted with dichloromethane/methanol/sat.aq. ammonium hydroxide solution (100:10:1) and brine. The organic phasewas separated, dried over sodium sulfate, concentrated andchromatographed over silica gel (dichloromethane-5%methanol/dichloromethane solvent gradient) to give the free base whichwas dissolved in ethyl acetate/methanol (1:1) and precipitated with oneequivalent of oxalic acid in ethyl acetate to give the title compound in90% yield as a white solid. mp. 125°-127° C. FDMS m/e=408 (M⁺ of freebase). α[D]₅₈₉ =-6.47 (c=0.49, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.76     62.88                                                H              6.28      6.59                                                 N              8.45      8.60                                                 ______________________________________                                    

EXAMPLE 143 Preparation of1-(4-indolyloxy)-4-(4-(2-naphthyl)piperidin-1-yl)butane ethanedioate

A solution of 1-chloro-4-(4-indolyloxy)butane (prepared from4-hydroxy-1H-indole and 1-bromo-4-chlorobutane),4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate inacetonitrile was heated at reflux for 12 h. The mixture was cooled anddiluted with ethyl acetate, and the organic layer was separated andwashed with brine. The crude residue was purified by silica gelchromatography (dichloromethane/5% methanol in dichloromethane gradienteluent). The resulting free base was dissolved in ethyl acetate andprecipitated with one equivalent of oxalic acid in ethyl acetate, togive the title compound in 48% overall yield as a tan solid. mp.113°-115° C. FDMS m/e=398 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.29     71.40                                                H              6.60      6.47                                                 N              5.73      5.95                                                 ______________________________________                                    

EXAMPLE 144 Preparation of1-(4-indolyloxy)-5-(4-(2-naphthyl)piperidin-1-yl)pentane ethanedioate

A solution of 1-chloro-5-(4-indolyloxy)pentane, 4-(2-naphthyl)piperidineand 3 equivalents of potassium carbonate in acetonitrile was heated atreflux for 12 h. The mixture was cooled, diluted with ethyl acetate, andthe organic layer was separated and washed with brine. The crude residuewas purified by silica gel chromatography (dichloromethane/5% methanolin dichloromethane gradient eluent). The resulting free base wasdissolved in ethyl acetate and precipitated with one equivalent ofoxalic acid in ethyl acetate, to give the title compound in 47% overallyield as a white solid. mp. 178°-180° C. FDMS m/e=412 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.69     71.93                                                H              6.82      6.79                                                 N              5.57      5.69                                                 ______________________________________                                    

EXAMPLE 145 Preparation of1-(4-indolyloxy)-2-(4-(2-naphthyl)piperidin-1-yl)ethane ethanedioate

A solution of 1-chloro-2-(4-indolyloxy)ethane, 4-(2-naphthyl)piperidineand 3 equivalents of potassium carbonate in acetonitrile was heated atreflux for 12 h. The mixture was cooled, diluted with ethyl acetate, andthe organic layer was separated and washed with brine. The crude residuewas purified by silica gel chromatography (dichloromethane/5% methanolin dichloromethane gradient eluent). The resulting free base wasdissolved in ethyl acetate and precipitated with one equivalent ofoxalic acid in ethyl acetate, to give the title compound in 29% overallyield as a white solid. mp. 119°-120° C. FDMS m/e=370 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.42     70.52                                                H              6.13      6.35                                                 N              6.08      5.88                                                 ______________________________________                                    

Preparation 20 Preparation of5-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene

A solution of 5-chlorobenzo[b]thiophene (0.600 g, 3.56 mmol) in freshlydistilled tetrahydrofuran (20 ml) was treated with n-butyllithium (1.2M,2.94 ml, 3.56 mmol) under nitrogen atmosphere at -78° C. The anion wasallowed to stir for 60 minutes, and then was treated with a solution ofN-t-butoxycarbonyl-4-piperidone (0.779 g, 3.91 mmol) in tetrahydrofuran(5.0 ml) and allowed to warm to 0° C. The reaction was quenched withsat. sodium bicarbonate, diluted with hexanes/diethyl ether (1:1),separated, the organic phase washed with brine and dried over sodiumsulfate. Flash chromatography (silica gel, toluene/ethyl acetate 9:1)gave 1.09 g of a colorless foam which was contaminated with 20%unreacted piperidone. FDMS m/e=367.

Preparation 21 Preparation of5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene

A solution of the product of Preparation 20 (0.998 g, 2.72 mmol) inmethylene chloride (10 ml) was treated with 2.0 ml of trifluoroaceticacid and stirred at 23° C. for 3 hours. The reaction was concentrated toa foam under reduced pressure and the residue chromatographed (silicagel, chloroform/methanol 95:5) to give 0.444 g (65%) of a tan coloredsolid. A sample was dissolved in ethyl acetate, treated with 1.0equivalent of oxalic acid and evaporated. mp=235°-237 C., FDMS m/e=250(M⁺ of free base)

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              53.02     53.06                                                H              4.15      4.27                                                 N              4.12      4.10                                                 ______________________________________                                    

Preparation 22 Preparation of 3-bromo-5-chlorobenzo[b]thiophene

A solution of bromine (0.31 g, 1.95 mmol) in 1.0 ml glacial acetic acidwas added to a stirred solution of 5-chlorobenzo[b]thiophene (0.300 g,1.77 mmol)in glacial acetic acid (1.0 ml) under nitrogen atmosphere. Thereaction was heated to 50° C. for 4 hours, the volatiles removed underreduced pressure, the residue diluted in methylene chloride, washed withaq. sodium bicarbonate and with brine and dried over sodium sulfate.Evaporation gave 0.335 g (76%) of a tan solid. mp 85°-86 C., FDMSm/e=249 (M+2).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              38.82     39.12                                                H              1.63      1.72                                                 ______________________________________                                    

Preparation 23 Preparation of5-chloro-3-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene

A flame dried 50 ml flask was charged with n-butyllithium (1.55 ml, 1.86mmol) in diethyl ether (5.0 ml) under nitrogen atmosphere. The internaltemperature was lowered to -78° C. and treated with an ethereal solution(10 ml) of 3-bromo-5-chlorobenzo[b]thiophene (0.418 g, 1.68 mmol) Afterstirring at -78° C. for 60 minutes the rust-colored solution was treatedwith N-t-butoxycarbonyl-4-piperidone (0.401 g, 2.0 mmol) in diethylether (5.0 ml) and stirring continued for 2 hours at -78° C. followed byslow warming to -20° C. over 55 minutes. The reaction was quenched withsaturated sodium bicarbonate, diluted with additional diethyl ether,separated, the organics washed with brine, and dried over sodiumsulfate. Chromatography (silica, toluene/ethyl acetate 9:1) gave 0.36 gof a colorless foam which was contaminated with a small amount ofunreacted piperidone. FDMS m/e=367 (M⁺)

Preparation 24 Preparation of5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene

A solution of the product of Preparation 23 (0.320 g, 0.86 mmol) inmethylene chloride (3.0 ml) was treated with 2.0 ml of trifluoroaceticacid and stirred at 23° C. for 4 hours. The reaction was concentrated toa foam under reduced pressure and the residue chromatographed (silicagel, chloroform/methanol 95:5) to give 0.140 g (64%) of a foam. Thesample was dissolved in ether, treated with excess hydrochloric acid inether and evaporated to an orange solid. mp=230°-235° C., FDMS m/e=250(M⁺ of free base)

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              54.55     54.81                                                H              4.58      4.77                                                 N              4.89      5.14                                                 ______________________________________                                    

Preparation 25 Preparation of 2-(3-chloro-1-thiophenyl)acetaldehydediethyl acetal

A three-neck round bottom flask was charged with 3-chloro-thiophenol(20.0 g, 0.138 mol) and potassium carbonate (21 g, 0.15 mol) in acetone(220 ml) and treated with a dropwise addition of bromoacetaldehydediethyl acetal. After stirring for 17 hours at 23° C., the slurry wasfiltered through a small plug of celite, the filtrate evaporated underreduced pressure and the residue diluted with diethyl ether and water.The organics were washed with brine, dried over sodium sulfate, andevaporated to a rust-colored oil weighing 35.1 g (97%). FDMS m/e=260(M⁺).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              55.27     55.37                                                H              6.57      6.35                                                 ______________________________________                                    

Preparation 26 Preparation of a 1:1 mixture of4-chloro/6-chlorobenzo[b]thiophene

A one neck round bottom flask was charged with polyphosphoric acid (12.8g) in refluxing chlorobenzene (100 ml) and treated by the dropwiseaddition of 2-(3-chloro-1-thiophenyl)acetaldehyde diethyl acetal (6.0 g,0.023 mol) in chlorobenzene (20 ml). The slurry was stirred at refluxfor 1 hour, cooled to 23° C. and the organics decanted from the mixture.After washing with brine, drying over sodium sulfate and evaporation,2.75 g (71%) of a thin, rust-colored oil was isolated.

Preparation 27 Preparation of a 1:1 mixture of4-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiopheneand6-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene

A solution of a 1:1 mixture of4-chlorobenzo[b]thiophene/6-chlorobenzo[b]thiophene (1.5 g, 8.92 mmol)in freshly distilled tetrahydrofuran (30.0 ml) was treated withn-butyllithium (1.3M, 7.55 ml, 9.82 mmol) under nitrogen atmosphere at-78° C. The anion was allowed to stir for 60 minutes then was treatedwith a solution of N-t-butoxycarbonyl-4-piperidone (1.95 g, 9.82 mmol)in tetrahydrofuran (10.0 ml) and allowed to warm to -0.5° C. Thereaction was quenched with 0.5M sodium hydrogen sulfate, diluted withhexanes/diethyl ether (1:1), separated, the organic phase washed withbrine and dried over sodium sulfate. Flash chromatography (silica gel,toluene/ethyl acetate 9:1) gave 0.64 g of a colorless solid which wasidentified by its ¹ H NMR spectrum as the 4-chloro regioisomer.

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.77     59.01                                                H              6.03      6.20                                                 N              3.81      3.87                                                 ______________________________________                                    

The second fraction isolated provided 1.04 g of a colorless foam whichwas identified as the 6-chloro regioisomer.

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.77     58.97                                                H              6.03      6.08                                                 N              3.81      3.98                                                 ______________________________________                                    

Preparation 28 Preparation of4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene

A solution of4-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene(0.290 g, 0.79 mmol) in methylene chloride (4.0 ml) was treated with 1.5ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. Thereaction was concentrated to a foam under reduced pressure and theresidue chromatographed (silica gel, chloroform/methanol 95:5) to give0.175 g (88%) of a tan powder. FDMS m/e=250 (M⁺ of free base)

Preparation 29 Preparation of6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene

A solution of6-chloro-2-(4-hydroxy-N-t-butoxycarbonylpiperidin-4-yl)benzo[b]thiophene(1.04 g, 2.83 mmol) in methylene chloride (30.0 ml) was treated with4.36 ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. Thereaction was concentrated to a foam under reduced pressure and theresidue chromatographed (silica gel, CHCl₃ /MeOH 95:5) to give 0.640 g(90%) of a tan powder. FDMS m/e=250 (M⁺ of free base)

Preparation 30 Preparation of7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

Potassium hydroxide (6.89 g, 0.12 mol) was dissolved in methanol (30mL). To the solution were added 7-chloroindole (4.65 g, 0.031 mol),4-piperidone hydrochloride hydrate (9.48 g, 0.061 mol). The mixture wasstirred at reflux temperature under nitrogen for about a day, and wascooled and diluted with 50 mL of water, added dropwise. The solid wascollected, washed with water and vacuum dried. Yield 5.6 g (78%) as ayellow solid. mp 197°-201° C. FDMS m/e=232 (M+).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.10     66.98                                                H              5.63      5.54                                                 N              12.04     11.86                                                ______________________________________                                    

Preparation 31 Preparation of 7-chloro-3-(piperidin-4-yl)-1H-indole

7-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.0 g, 8.62 mmol)and 0.5 g of platinum oxide were added to 100 mL of ethanol and themixture was shaken under about 50 psi hydrogen at about ambienttemperature for about a day. The mixture was filtered and the filtrateconcentrated to yield a solid comprising the desired product. Yield 1.64g (81%) as a yellow solid. FDMS m/e=234 (M+).

EXAMPLE 146 Preparation of3-[4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propanehydrochloride

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.444 g, 2.13mmol) and the hydrochloride salt of5-chloro-3-(1,2,3,6-tetrahydropyridin-1-yl)-1H-indole (0.500 g, 2.13mmol) in the presence of 3.0 equivalents of potassium carbonate (0.881g, 6.39 mmol) in dimethylformamide at 90° C. Yield 0.320 g (34%) of theHCl salt as a light brown solid. mp 167°-172° C. FDMS m/e=407 (M+ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.86     64.95                                                H              6.12      6.17                                                 N              9.45      9.32                                                 ______________________________________                                    

EXAMPLE 147 Preparation of(2S)-(-)-3-[4-(6-trifluoromethyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanolethanedioate

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.716 g, 3.78mmol) and 6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-1-yl)-1H-indole(1.0 g, 3.78 mmol) using ethanol as reaction solvent. Yield 0.340 g(20%) as a tan foam, which was treated with 1.0 equivalent of oxalicacid in diethyl ether and evaporated to a tan solid, mp 135°-139° C.FDMS m/e=455 (M+ of free base). α[D]₅₈₉ =-13.1 (c=1.06,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.47     60.04                                                H              4.76      4.95                                                 N              7.70      7.58                                                 ______________________________________                                    

EXAMPLE 148 Preparation of2-[4-(6-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)ethaneethanedioate

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-2-(1H-indole-4-oxy)ethane (0.359 g, 1.85mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate(0.51 g, 3.7 mmol) in dimethylformamide at 90° C. Yield 0.101 g (14%) ofa tan foam. The oxalate salt was prepared by treating the free base with1.0 equivalent of oxalic acid in diethyl ether and evaporating. mp120°-124° C. (browns) FDMS m/e=391 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.31     62.09                                                H              5.02      5.10                                                 N              8.72      8.66                                                 ______________________________________                                    

EXAMPLE 149 Preparation of4-[4-(6-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)butane

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-4-(1H-indole-4-oxy)butane (0.479 g, 2.15mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500g, 2.13 mmol) in the presence of 2.5 equivalents of potassium carbonate(0.742 g, 5.38 mmol) in dimethylformamide at 90° C. Yield 0.220 g (24%)of a tan foam. FDMS m/e=420 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.54     71.11                                                H              6.19      6.29                                                 N              10.00     10.54                                                ______________________________________                                    

EXAMPLE 150 Preparation of3-[4-(7-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl)-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15mmol) and 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate(0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.190 g (22%)of a tan foam. mp 166°-169° C. FDMS m/e=405 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.01     70.71                                                H              5.96      6.01                                                 N              10.35     10.28                                                ______________________________________                                    

EXAMPLE 151 Preparation of 3-[4-(6-chloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15mmol) and 6-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) inthe presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3mmol) in dimethylformamide at 90° C. Yield 0.330 g (37%) of a colorlessfoam. FDMS m/e=407 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.66     70.36                                                H              6.42      6.47                                                 N              10.30     10.15                                                ______________________________________                                    

EXAMPLE 152 Preparation of(2S)-(+)-3-[4-(5-chloro-2-benzo[b]thiophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.075 g, 0.042mmol), and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene(0.100 g, 0.042 mmol) using ethanol as reaction solvent. Yield 0.103 g(58%) of an orange oil. FDMS m/e=438 (M⁺ of free base). α[D]₅₈₉ =+7.3(c=0.95, dimethylsulfoxide)

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.67     65.43                                                H              5.28      5.30                                                 N              6.38      6.23                                                 ______________________________________                                    

EXAMPLE 153 Preparation of(2S)-(+)-3-[4-(5-chloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-chloro-3-(piperidin-4-yl)-1H-indole using ethanol as the reactionsolvent. Yield 0.380 g (42%) as a yellowish foam. mp 109°-114° C. (dec)FDMS m/e=423 (M⁺ of free base). α[D]₅₈₉ =+6.5 (c=1.04,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.99     67.34                                                H              6.13      6.12                                                 N              9.90      9.57                                                 ______________________________________                                    

EXAMPLE 154 Preparation of(2S)-(+)-3-[4-(7-chloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.406 g, 2.13mmol) and 7-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol)using ethanol as reaction solvent. Yield 0.325 g (35%) as a colorlesspowder. mp 186°-189° C. FDMS m/e=423 (M⁺ of free base). α[D]₅₈₉ =+8.44(c=1.09, dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.00     68.23                                                H              6.18      6.28                                                 N              9.91      10.20                                                ______________________________________                                    

EXAMPLE 155 Preparation of(2S)-(+)-3-[4-(5-chloro-3-benzo[b]thiophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.053 g, 0.028mmol) and the hydrochloride salt of5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.08 1 g,0.028 mmol) using ethanol as reaction solvent and 1.1 equivalents ofpotassium carbonate (0.043 g, 0.031 mmol). Yield 0.103 g (83%) of a tanfoam. mp 93°-97° C. FDMS m/e=438 (M⁺ of free base). α[D]₅₈₉ =+7.5(c=1.06, dimethylsufoxide)

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.67     65.75                                                H              5.28      5.33                                                 N              6.38      6.15                                                 ______________________________________                                    

EXAMPLE 156 Preparation of(2S)-(-)-3-[4-(4-chloro-2-benzo[b]thiophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanolethanedioate

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.129 g, 0.068mmol) and 4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl) benzo[b]thiophene(0.170 g, 0.068 mmol) using ethanol as reaction solvent. Yield 0.105 g(34%) of a tan powder. FDMS m/e=438 (M⁺ of free base). A sample wasdissolved in ethyl acetate and treated with 1.0 equivalent of oxalicacid and evaporated to an orange powder. mp 138°-142° C. (dec) α[D]₅₈₉=-5.3 (c=1.13, dimethylsufoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              59.03     59.32                                                H              4.76      4.66                                                 N              5.29      5.27                                                 ______________________________________                                    

EXAMPLE 157 Preparation of(2R)-(-)-3-[4-(6-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(5-quinolinyloxy-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (R)-5-(oxiranylmethoxy)quinoline (0.495 g, 2.46 mmol)and 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.519 g, 2.33mmol) using ethanol as reaction solvent. Yield 0.840 g (87%) of a tanpowder. FDMS m/e=433 (M⁺ of free base). mp 221°-223° C. α[D]₅₈₉ =-9.9(c=1.00, dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.20     69.00                                                H              5.58      5.32                                                 N              9.68      9.78                                                 ______________________________________                                    

EXAMPLE 158 Preparation of(2S)-(+)-3-(4-(6-methyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl)-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.260 g (35%) asan orange foam. mp 99°-103° C. (dec). FDMS m/e=401 (M+ of free base).α[D]₅₈₉ =+5.1 (c=0.98, dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              74.79     74.50                                                H              6.78      6.76                                                 N              10.47     10.22                                                ______________________________________                                    

EXAMPLE 159 Preparation of(2S)-(+)-3-[4-(7-methyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl)-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.292 g (39%) asan orange foam. mp 155°-158° C. FDMS m/e=401 (M+ of free base). α[D]₅₈₉=+5.9 (c=1.05, dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              74.79     74.54                                                H              6.78      6.85                                                 N              10.47     10.33                                                ______________________________________                                    

EXAMPLE 160 Preparation of(2S)-(+)-3-[4-(6-chloro-2-benzo[b]thiophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.166 g, 0.088mmol) and 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene(0.200 g, 0.080 mmol) using ethanol as reaction solvent. Yield 0.122 g(35%) of a tan powder. FDMS m/e=438 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.67     65.43                                                H              5.28      5.29                                                 N              6.38      6.67                                                 ______________________________________                                    

EXAMPLE 161 Preparation of1-(4-indolyloxy)-3-[4-(4-cyclopropylmethoxy-1H-indol-3-yl)piperidin-1-yl]propaneethanedioate monohydrate

The title compound was prepared according to Example 99 from1-chloro-3-(1H-indole-4-oxy)propane and4-(4-cyclopropylmethoxy-1H-indol-3-yl)piperidine (which was prepared bycondensing 4-cyclopropylmethoxyindole with 4-piperidone monohydratehydrochloride in refluxing methanol with potassium hydroxide, followedby reduction of the unsaturation with palladium on carbon in methanol).The resulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 57% overall yieldas a white foam. FDMS m/e=443 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.32     65.38                                                H              6.76      6.73                                                 N              7.62      7.72                                                 ______________________________________                                    

EXAMPLE 162 Preparation of1-(4-indolyloxy)-3-[4-(4-cyclopropylmethoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and4-(4-cyclopropylmethoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridine (whichwas prepared by condensing 4-cyclopropylmethoxyindole with 4-piperidonemonohydrate hydrochloride in refluxing methanol with potassiumhydroxide). The resulting free base was dissolved in ethyl acetate, andprecipitated with one equivalent of oxalic acid in ethyl acetate in 20%overall yield as a white foam FDMS m/e=441 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.78     68.07                                                H              6.26      6.41                                                 N              7.90      7.91                                                 ______________________________________                                    

EXAMPLE 163 Preparation of1-(4-indolyloxy)-3-[4-hydroxy-4-(1H-indol-5-yl)piperidin-1-yl]propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and4-hydroxy-4-(1H-indol-5-yl)piperidine (which was prepared by treatmentof the potassium salt of 5-bromoindole with tert-butyllithium intetrahydrofuran at -78° C., followed by quenching withN-benzyl-4-piperidone in tetrahydrofuran, and hydrogenolysis of theresulting adduct with palladium on carbon in ethanol, to give thedesired piperidine in 20% yield). The resulting free base was dissolvedin ethyl acetate, and precipitated with one equivalent of oxalic acid inethyl acetate in 68% overall yield as a foam. FDMS m/e=390 (M⁺ of freebase).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.12     65.47                                                H              6.10      5.97                                                 N              8.76      9.07                                                 ______________________________________                                    

EXAMPLE 164 Preparation of1-(4-indolyloxy)-3-[4-hydroxy-4-(2-naphthyl)piperidin-1-yl]propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)-piperdine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 24% overall yieldas a foam. FDMS m/e=400 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.56     68.84                                                H              6.16      6.09                                                 N              5.71      5.55                                                 ______________________________________                                    

EXAMPLE 165 Preparation of1-(4-indolyloxy)-3-[4-(6-methoxynaphth-2-yl)piperidin-1-yl)propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and4-[2-(6-methoxynaphthyl)]piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 60% overall yield as a foam. FDMSm/e=414 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.03     68.79                                                H              6.39      6.09                                                 N              5.55      5.30                                                 ______________________________________                                    

EXAMPLE 166 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-(6-methoxynaphth-2-yl)piperidin-1-yl]-2-propanol ethanedioate

The title compound was prepared according to Example 1 from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-[2-(6-methoxynaphthyl)]piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 66% overall yield as a foam. FDMSm/e=430 (M⁺ of free base). α[D]₅₈₉ =-5.64 (c=0.53, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.91     66.64                                                H              6.20      6.24                                                 N              5.38      5.14                                                 ______________________________________                                    

EXAMPLE 167 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrothiophene-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared according to Example 121 from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-methoxyspiro[benzodihydrothiophene-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 83% overall yield. mp.123°-125° C. FDMS m/e=424 (M⁺ of free base). α[D]₅₈₉ =-14.71 (c=0.48,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.69     60.63                                                H              5.88      6.17                                                 N              5.44      5.22                                                 ______________________________________                                    

EXAMPLE 168 Preparation of1-(4-indolyloxy)-3-(4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 33% overall yield as afoam. FDMS m/e=482 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.12     66.82                                                H              5.63      5.49                                                 N              4.89      5.05                                                 ______________________________________                                    

EXAMPLE 169 Preparation of1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrothiophene-1(3H),4,-piperidin]-1'-yl)propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and5-methoxyspiro[benzodihydrothiophene-1(3H),4,-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 57% overall yield. mp.125°-126° C. FDMS m/e=408 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.63     62.46                                                H              6.06      6.26                                                 N              5.62      5.77                                                 ______________________________________                                    

EXAMPLE 170 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 73% overall yield. mp215°-217° C. (decomp). FDMS m/e=468 (M⁺ of free base). α[D]₅₈₉ =-65.93(c=0.55, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.66     66.46                                                H              5.41      5.44                                                 N              5.02      4.98                                                 ______________________________________                                    

EXAMPLE 171 Preparation of1-(4-indolyloxy)-3-(4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propane ethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 42% overall yield. mp226°-228° C. (decomp). FDMS m/e=452 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.62     68.39                                                H              5.57      5.71                                                 N              5.16      5.13                                                 ______________________________________                                    

EXAMPLE 172 Preparation of1-(4-indolyloxy)-3-(4-hydroxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of1-(4-indolyloxy)-3-(4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propanein methanol was treated with a catalytic amount of 5% palladium oncarbon, and hydrogen (one atmosphere) overnight. The mixture wasfiltered through a pad of Celite and concentrated, to give the freebase, which was dissolved in ethyl acetate and precipitated with oneequivalent of oxalic acid to give the title compound in 85% overallyield as a foam. FDMS m/e=392 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.23     62.41                                                H              5.43      5.43                                                 N              5.81      5.55                                                 ______________________________________                                    

EXAMPLE 173 Preparation of1-(4-indolyloxy)-3-(4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,4-phenylspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 38% overall yield as afoam. FDMS m/e=438 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.44     70.29                                                H              6.10      6.10                                                 N              5.30      5.19                                                 ______________________________________                                    

EXAMPLE 174 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 78% overallyield. FDMS m/e=450 (M⁺ of free base). α[D]₅₈₉ =-9.26 (c=0.32,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              60.00     59.71                                                H              5.22      5.43                                                 N              5.18      5.08                                                 ______________________________________                                    

EXAMPLE 175 Preparation of1-(4-indolyloxy)-3-(6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 45% overall yield as afoam. FDMS m/e=434 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.83     62.02                                                H              5.38      5.60                                                 N              5.34      5.37                                                 ______________________________________                                    

EXAMPLE 176 Preparation of1-(4-indolyloxy)-3-(1,5-dihydrospiro[4H-2-benzopyran-4,4'-piperidin]-1'-yl)propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and1,5-dihydrospiro[4H-2-benzopyran-4,4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 69% overall yield as afoam. FDMS m/e=376 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.94     66.71                                                H              6.48      6.60                                                 N              6.00      5.92                                                 ______________________________________                                    

EXAMPLE 177 Preparation of1-(4-indolyloxy)-3-(6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 39% overall yield as afoam. FDMS m/e=420 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.52     63.57                                                H              5.92      5.88                                                 N              5.49      5.22                                                 ______________________________________                                    

EXAMPLE 178 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6,7-ethylenedioxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 54% overallyield. FDMS m/e=436 (M⁺ of free base). α[D]₅₈₉ =-12.70 (c=0.55,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              61.59     61.89                                                H              5.74      5.95                                                 N              5.32      5.52                                                 ______________________________________                                    

EXAMPLE 179 Preparation of1-(4-indolyloxy)-3-(6-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 62% overall yield as afoam. FDMS m/e=482 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.12     66.93                                                H              5.63      5.66                                                 N              4.89      4.72                                                 ______________________________________                                    

EXAMPLE 180 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-ethoxyspiro[benzodihyrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 70% overall yield as afoam. FDMS m/e=422 (M⁺ of free base). α[D]₅₈₉ =-5.25 (c=0.57, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.27     63.56                                                H              6.29      6.37                                                 N              5.47      5.26                                                 ______________________________________                                    

EXAMPLE 181 Preparation of1-(4-indolyloxy)-3-(4-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,4-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 38% overall yield as afoam. FDMS m/e=406 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.31     65.12                                                H              6.50      6.40                                                 N              5.64      5.45                                                 ______________________________________                                    

EXAMPLE 182 Preparation of1-(4-indolyloxy)-3-(4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 70% overall yield as afoam. FDMS m/e=468 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.80     68.55                                                H              6.13      6.15                                                 N              5.01      4.89                                                 ______________________________________                                    

EXAMPLE 183 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 91% overall yield as afoam. FDMS m/e=436 (M⁺ of free base). α[D]₅₈₉ =-5.50 (c=0.55, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.79     68.58                                                H              6.47      6.55                                                 N              6.42      6.28                                                 ______________________________________                                    

EXAMPLE 184 Preparation of1-(4-indolyloxy)-3-(6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-3-one and 3equivalents of potassium carbonate in acetonitrile was heated at refluxfor 12 h. The mixture was cooled, diluted with ethyl acetate, and theorganic layer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 36% overall yield as afoam. FDMS m/e=420 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.52     63.59                                                H              5.92      5.82                                                 N              5.49      5.11                                                 ______________________________________                                    

EXAMPLE 185 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 59% overall yield as afoam. FDMS m/e=422 (M⁺ of free base). α[D]₅₈₉ =-3.58 (c=0.56, methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.27     62.99                                                H              6.29      6.29                                                 N              5.47      5.16                                                 ______________________________________                                    

EXAMPLE 186 Preparation of1-(4-indolyloxy)-3-(6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

A solution of 1-chloro-3-(1H-indole-4-oxy)propane,6-ethoxyspiro[benzodihydrofuran-1(3H),4'-piperidine] and 3 equivalentsof potassium carbonate in acetonitrile was heated at reflux for 12 h.The mixture was cooled, diluted with ethyl acetate, and the organiclayer was separated and washed with brine. The crude residue waspurified by silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent). The resulting free base was dissolvedin ethyl acetate and precipitated with one equivalent of oxalic acid inethyl acetate, to give the title compound in 52% overall yield as afoam. FDMS m/e=406 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.31     65.06                                                H              6.50      6.48                                                 N              5.64      5.28                                                 ______________________________________                                    

EXAMPLE 187 Preparation of1-(4-indolyloxy)-3-[4-(3,4-ethylenedioxyphenyl)piperidin-1-yl]propaneethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and4-(3,4-ethylenedioxyphenyl)piperidine. The resulting free base wasdissolved in ethyl acetate, and precipitated with one equivalent ofoxalic acid in ethyl acetate in 59% overall yield as a foam. FDMSm/e=392 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     65.08                                                H              6.27      6.57                                                 N              5.81      5.68                                                 ______________________________________                                    

EXAMPLE 188 Preparation of1-(4-indolyloxy)-3-[4-(2-naphthyl)piperidin-1-yl]propane ethanedioate

The title compound was prepared in similar fashion from1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)piperidine. Theresulting free base was dissolved in ethyl acetate, and precipitatedwith one equivalent of oxalic acid in ethyl acetate in 57% overall yieldas a white solid. mp. 145°-146° C. FDMS m/e=384 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.87     71.14                                                H              6.37      6.30                                                 N              5.90      5.62                                                 ______________________________________                                    

EXAMPLE 189 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(5-methylspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared according to Example 1 from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and5-methylspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 72% overall yield as afoam. FDMS m/e=392 (M⁺ of free base). α[D]₅₈₉ =-16.89 (c=0.53,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.72     65.00                                                H              6.27      6.30                                                 N              5.81      5.80                                                 ______________________________________                                    

EXAMPLE 190 Preparation of(2S)-(-)-1-(4-indolyloxy)-3-(4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)-2-propanolethanedioate

The title compound was prepared in similar fashion from(S)-(+)-4-(oxiranylmethoxy)-1H-indole and4-benzyloxyspiro[benzodihydrofuran-1(3H),4'-piperidine]. The resultingfree base was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 90% overall yield as afoam. FDMS m/e=484 (M⁺ of free base). α[D]₅₈₉ =-15.32 (c=0.52,methanol).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.89     67.13                                                H              5.96      6.23                                                 N              4.88      4.96                                                 ______________________________________                                    

EXAMPLE 191 Preparation of1-(4-indolyloxy)-3-(benzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidin]-1'-yl)propaneethanedioate

The title compound was prepared according to Example 121 from1-chloro-3-(1H-indole-4-oxy)propane andbenzo[c]spiro[benzodihydrofuran-1(3H),4'-piperidine]. The resulting freebase was dissolved in ethyl acetate, and precipitated with oneequivalent of oxalic acid in ethyl acetate in 50% overall yield as awhite solid. mp. 159°-160° C. FDMS m/e=412 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.31     69.55                                                H              6.02      6.28                                                 N              5.57      5.64                                                 ______________________________________                                    

PREPARATION 32 Preparation of5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 5-methoxyindole (5.0 g, 34 mmol) and 4-piperidonehydrochloride hydrate (10.0 g, 65 mmol). The product was isolated as ayellow solid. Yield 6.1 g (79%). mp 191°-195° C. FDMS m/e=228 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              73.66     73.38                                                H              7.06      7.08                                                 N              12.27     12.36                                                ______________________________________                                    

Preparation 33 Preparation of6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6-methoxyindole (2.0 g, 14 mmol) and 4-piperidonehydrochloride hydrate (4.2 g, 27 mmol). The product was isolated as ayellow solid. Yield 2.8 g (90%). mp 190°-193° C. FDMS m/e=228 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              73.66     73.44                                                H              7.06      7.16                                                 N              12.27     12.37                                                ______________________________________                                    

Preparation 34 Preparation of6-chloro-5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6-chloro-5-methoxyindole (2.0 g, 11 mmol) and4-piperidone hydrochloride hydrate (3.4 g, 22 mmol). The product wasisolated as a yellow solid. Yield 2.4 g (83%). mp 222°-224° C. FDMSm/e=264 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.00     64.12                                                H              5.75      5.86                                                 N              10.66     10.57                                                ______________________________________                                    

Preparation 35 Preparation of6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole monohydrate

The title compound was prepared in a fashion similar to that describedin Preparation 31 from6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.1 g,7.9 mmol). The product was isolated as a yellow solid. Yield 1.2 g(57%). mp 210°-214° C. FDMS m/e=268 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.73     58.70                                                H              5.98      5.44                                                 N              9.78      9.96                                                 ______________________________________                                    

Preparation 36 Preparation of 6,7-dichloro-3-(piperidin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 31 from6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (4.5 g, 16.8mmol). The product was isolated as a white solid. Yield 4.1 g (91%). mp254°-257° C. FDMS m/e=270 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.01     58.25                                                H              5.24      5.42                                                 N              10.41     10.64                                                ______________________________________                                    

Preparation 37 Preparation of6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6,7-dichloroindole (1.4 g, 7.5 mmol) and4-piperidone hydrochloride hydrate (2.3 g, 15 mmol). The product wasisolated as a white solid. Yield 1.8 g (89%). mp 252°-254° C. FDMSm/e=268 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              58.45     58.71                                                H              4.53      4.64                                                 N              10.49     10.33                                                ______________________________________                                    

Preparation 38 Preparation of7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 7-chloroindole (0.70 g, 4.6 mmol) and4-piperidone hydrochloride hydrate (1.4 g, 9.2 mmol). The product wasisolated as a yellow solid. Yield 0.80 g (75%). mp 205°-208° C. FDMSm/e=234 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.10     67.06                                                H              5.63      5.85                                                 N              12.04     12.01                                                ______________________________________                                    

Preparation 39 Preparation of6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6-nitroindole (6.0 g, 37 mmol) and 4-piperidonehydrochloride hydrate (11.4 g, 74 mmol). The product was isolated as anorange solid. Yield 8.8 g (97%). mp 247°-250° C. (dec.) FDMS m/e=243 (M⁺of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              64.19     64.37                                                H              5.39      5.40                                                 N              17.27     17.50                                                ______________________________________                                    

Preparation 40 Preparation of5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 5-chloroindole (3.0 g, 20 mmol) and 4-piperidonehydrochloride hydrate (6.0 g, 40 mmol). The product was isolated as ayellow solid. Yield 1.45 g (31%). mp 185°-188° C. FDMS m/e=234 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.10     67.38                                                H              5.63      5.58                                                 N              12.04     12.25                                                ______________________________________                                    

Preparation 41 Preparation of6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6-trifluoromethylindole (4.0 g, 22 mmol) and4-piperidone hydrochloride hydrate (6.6 g, 43 mmol). The product wasisolated as a white solid. Yield 3.7 g (64%). mp °C. FDMS m/e=266 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.15     62.90                                                H              4.92      4.96                                                 N              10.52     10.57                                                ______________________________________                                    

Preparation 42 Preparation of 6-fluoro-3-(piperidin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 31 from6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (19.2 g, 89 mmol).The product was isolated as a white solid. Yield 18.5 g (96%). mp234°-236° C. FDMS m/e=218 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.53     71.77                                                H              6.93      7.11                                                 N              12.83     13.00                                                ______________________________________                                    

Preparation 43 Preparation of6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole

The title compound was prepared in a fashion similar to that describedin Preparation 30 from 6-chloroindole (4.0 g, 26 mmol) and 4-piperidonehydrochloride hydrate (8.0 g, 52 mmol). The product was isolated as ayellow solid. Yield 3.7 g (61%). mp 181°-185° C. FDMS m/e=234 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              67.10     67.13                                                H              5.63      5.70                                                 N              12.04     12.18                                                ______________________________________                                    

Preparation 44 Preparation of 6-chloro-3-(piperidin-4-yl)-1H-indolehydrochloride

The title compound was prepared in a fashion similar to that describedin Preparation 31 from6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.0 g, 4.3 mmol).The product was isolated as a white solid. Yield 0.65 g (56%). mp290°-294° C. (dec.) FDMS m/e=234 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              57.58     57.30                                                H              5.95      6.15                                                 N              10.33     10.57                                                ______________________________________                                    

Preparation 45 Preparation of 6-nitro-3-(piperidin-4-yl)-1H-indoletrifluoroacetate

6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.4 g, 9.9 mmol)was stirred in trifluoroacetic acid (10 mL) at room temperature under anatmosphere of nitrogen. Triethylsilane (1.65 mL, 10.4 mmol) was slowlyadded. After an initial exotherm, the mixture was stirred at roomtemperature for 12 hours. The mixture was concentrated under reducedpressure to yield a dark residue. The crude product was crystallizedfrom ethanol to yield the title compound as a yellow crystalline solid.Yield 2.4 g (67%). mp 215°-217° C. FDMS m/e=245 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              50.14     50.03                                                H              4.49      4.56                                                 N              11.69     11.66                                                ______________________________________                                    

EXAMPLE 192 Preparation of3-[4-(6-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propaneethanedioate

To 5 mL of dry dimethylformamide were added6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.45 g, 2.2 mmol), potassiumiodide (0.36 g, 2.2 mmol) and sodium bicarbonate (0.54 g, 6.4 mmol). Themixture was stirred at 90°-100° C. under nitrogen for about 12 hours,and was then cooled and concentrated under reduced pressure. The residuewas partitioned between water and chloroform, and the chloroform layerwas dried (sodium sulfate) and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography with 95/5chloroform/methanol. The resulting free base was dissolved in 20 mL of a1:1 methanol/ethyl acetate mixture and one equivalent of oxalic acid inmethanol (5 mL) was added. The mixture was concentrated to yield agranular solid. Yield 137 mg (13%). mp 170°-174° C. FDMS m/e=405 (M⁺ offree base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.97     63.09                                                H              5.28      5.37                                                 N              8.47      8.39                                                 ______________________________________                                    

EXAMPLE 193 Preparation of(2S)-(+)-3-[4-(6-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

To 5 mL of dry ethanol were added6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.54 g, 6.61mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.25 g, 6.61 mmol). Themixture was heated at the reflux temperature for about 6 hours, and wasthen cooled and concentrated. The residue was purified by silica gelchromatography with 95/5 chloroform/methanol. The product was isolatedas a yellow foam. Yield 1.52 g (55%). mp 200°-202° C. FDMS m/e=421 (M⁺of free base). α[D]₅₈₉ =+4.39 (c=1.00, dimethylsulfoxide)

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.32     68.04                                                H              5.73      5.72                                                 N              9.96      9.85                                                 ______________________________________                                    

EXAMPLE 194 Preparation of3-[4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.45 g, 2.2 mmol) andpotassium carbonate (0.35 g, 2.5 mmol). The product was isolated as awhite foam. Yield 220 mg (25%). mp 198°-202° C. FDMS m/e=406 (M⁺ of freebase).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.01     71.24                                                H              5.96      6.09                                                 N              10.35     10.20                                                ______________________________________                                    

EXAMPLE 195 Preparation of3-[4-(6-trifluoromethyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g,1.9 mmol), 1-chloro-3-(1H-indole -4-oxy)propane (0.39 g, 1.9 mmol) andpotassium carbonate (0.29 g, 2.1 mmol). The product was isolated as awhite foam. Yield 0.53 g (64%). mp 190°-195° C. FDMS m/e=440 (M⁺ of freebase).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.33     68.08                                                H              5.50      5.64                                                 N              9.56      9.44                                                 ______________________________________                                    

EXAMPLE 196 Preparation of3-[4-(6-nitro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(0.50 g, 2.1 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.43 g, 2.1mmol) and potassium carbonate (0.32 g, 2.3 mmol). The product wasisolated as an orange granular solid. Yield 0.49 g (56%). mp 215°-225°C. FDMS m/e=416 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              69.21     69.02                                                H              5.81      5.90                                                 N              13.45     13.48                                                ______________________________________                                    

EXAMPLE 197 Preparation of(2S)-(+)-3-[4-(6-nitro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(1.00 g, 4.12 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.78 g,4.12 mmol). The product was isolated as an orange granular solid. Yield0.61 g (34%). mp 225°-230° C. FDMS m/e=432 (M⁺ of free base). α[D]₅₈₉=+1.98 (c=1.01, dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.65     66.37                                                H              5.59      5.70                                                 N              12.96     12.72                                                ______________________________________                                    

EXAMPLE 198 Preparation of(2S)-(+)-3-[4-(6,7-dichloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 3.7mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.71 g, 3.7 mmol). Theproduct was isolated as a white foam. Yield 1.17 g (69%). mp 140°-145°C. FDMS m/e=455 (M⁺ of free base). α[D]₅₈₉ =+4.59 (c=1.00,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              63.17     63.36                                                H              5.08      5.30                                                 N              9.21      9.47                                                 ______________________________________                                    

EXAMPLE 199 Preparation of3-[4-(7-chloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from 7-chloro-3-(piperidin-4-yl)-1H-indole (0.34 g, 1.25mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.275 g, 1.32 mmol) andpotassium carbonate (0.41 g, 3.0 mmol). The product was isolated as awhite foam. Yield 240 mg (47%). mp 178°-182° C. FDMS m/e=407 (M⁺ of freebase). HRMS: calc., 408.184265; found, 408.184300

EXAMPLE 200 Preparation of(2S)-(+)-3-[4-(7-chloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol)and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.41 g, 2.2 mmol). Theproduct was isolated as a white foam. Yield 370 mg (41%). mp 85°-90° C.FDMS m/e=421 (M+of free base). α[D]₅₈₉ =+3.62 (c=1.00,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.32     68.54                                                H              5.73      5.77                                                 N              9.96      9.72                                                 ______________________________________                                    

EXAMPLE 201 Preparation of(2S)-(+)-3-[4-(6-chloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6-chloro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.3mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.81 g, 4.3 mmol). Theproduct was isolated as a white foam. Yield 1.15 g (64%). mp 90°-95° C.FDMS m/e=423 (M⁺ of free base). α[D]₅₈₉ =+8.81 (c=0.98,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.00     67.90                                                H              6.18      6.22                                                 N              9.91      9.85                                                 ______________________________________                                    

EXAMPLE 202 Preparation of3-[4-(6,7-dichloro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 2.6mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.60 g, 2.9 mmol) andpotassium carbonate (0.48 g, 3.5 mmol). The product was isolated as awhite granular solid. Yield 220 mg (19%). mp 224°-227° C. FDMS m/e=439(M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.46     65.19                                                H              5.26      5.27                                                 N              9.54      9.35                                                 ______________________________________                                    

EXAMPLE 203 Preparation of3-[4-(6,7-dichloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g,3.0 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.64 g, 3.1 mmol) andpotassium carbonate (0.83 g, 6.0 mmol). The product was isolated as atan foam. Yield 278 mg, 21%. mp 160°-165° C. FDMS m/e=441 (M⁺ of freebase).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.16     65.43                                                H              5.70      5.60                                                 N              9.50      9.66                                                 ______________________________________                                    

EXAMPLE 204 Preparation of(2S)-(+)-3-[4-(6,7-dichloro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g,3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol).The product was isolated as a white solid. Yield 0.64 g (47%). mp192°-197° C. FDMS m/e=457 (M⁺ of free base). α[D]₅₈₉ =+6.46 (c=0.99,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              62.89     63.09                                                H              5.50      5.61                                                 N              9.17      9.22                                                 ______________________________________                                    

EXAMPLE 205 Preparation of(2S)-(+)-3-[4-(6-trifluoromethyl-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.50g, 1.9 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.35 g, 1.9mmol). The product was isolated as a white foam. Yield 250 mg (29%). mp100°-105° C. FDMS m/e=457 (M⁺ of free base). α[D]₅₈₉ =+8.13 (c=1.01,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              65.64     65.36                                                H              5.73      5.73                                                 N              9.19      9.28                                                 ______________________________________                                    

EXAMPLE 206 Preparation of3-[4-(6-trifluoromethyl-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 192 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.60g, 2.2 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.65 g, 2.2 mmol) andpotassium carbonate (0.46 g, 3.4 mmol). The product was isolated as awhite foam. Yield 165 mg (17%). mp 92°-97° C. FDMS m/e=442 (M⁺ of freebase).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              68.01     68.02                                                H              5.94      5.98                                                 N              9.52      9.70                                                 ______________________________________                                    

EXAMPLE 207 Preparation of(2S)-(+)-3-[4-(5-methoxy-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 3.1mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol). Theproduct was isolated as a yellow foam. Yield 245 mg (19%). mp 105°-110°C. FDMS m/e=417 (M⁺ of free base). α[D]₅₈₉ =+7.52 (c=1.01,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.92     71.70                                                H               6.52     6.62                                                 N              10.06     9.85                                                 ______________________________________                                    

EXAMPLE 208 Preparation of(2S)-(+)-3-[4-(6-chloro-5-methoxy-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from6-chloro-5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g,3.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.60 g, 3.2 mmol).The product was isolated as a yellow foam. Yield 260 mg (19%). mp115°-120° C. FDMS m/e=452 (M⁺ of free base). α[D]₅₈₉ =+6.62 (c=1.03,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.44     66.55                                                H              5.80      5.94                                                 N              9.30      9.24                                                 ______________________________________                                    

EXAMPLE 209 Preparation of(2S)-(+)-3-[4-(6-methoxy-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.80 g, 3.5mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.66 g, 3.5 mmol). Theresulting free base was recrystallized from methanol to yield a whitecrystalline solid. Yield 0.63 g (43%). mp 155°-160° C. FDMS m/e=417 (M⁺of free base). α[D]₅₈₉ =+4.30 (c=0.98, methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.92     71.88                                                H               6.52      6.61                                                N              10.06     10.11                                                ______________________________________                                    

EXAMPLE 210 Preparation of(2S)-(+)-3-[4-(5-fluoro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 5-fluoro-3-(piperidin-4-yl)-1H-indole (0.87 g, 4.0mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.76 g, 4.0 mmol). Theproduct was isolated as a white foam. Yield 1.14 g (70%). mp 94°-97° C.FDMS m/e=407 (M⁺ of free base). α[D]₅₈₉ =+8.36 (c=1.00,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.74     70.58                                                H               6.43      6.68                                                N              10.31     10.23                                                ______________________________________                                    

EXAMPLE 211 Preparation of(2S)-(+)-3-[4-(6-fluoro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). Theproduct was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C.FDMS m/e=407 (M⁺ of free base). α[D]₅₈₉ =+7.97 (c=1.00,methanol/dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              70.74     70.49                                                H               6.43      6.36                                                N              10.31     10.53                                                ______________________________________                                    

EXAMPLE 212 Preparation of(2S)-(+)-3-[4-(6-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.88 g, 4.6 mmol). Theresulting free base was obtained as a yellow foam. Yield 1.2 g (64%). mp95°-100° C. FDMS m/e=405 (M⁺ of free base). α[D]₅₈₉ =5.15 (c=1.01,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.09     70.81                                                H               5.97      6.00                                                N              10.36     10.13                                                ______________________________________                                    

EXAMPLE 213 Preparation of(2S)-(+)-3-[4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.90 g, 4.8 mmol). Theresulting free base was isolated as a white foam. Yield 1.04 g (55%). mp95°-100° C. FDMS m/e=405 (M⁺ of free base). α[D]₅₈₉ =5.91 (c=1.01,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.09     70.86                                                H               5.97      6.06                                                N              10.36     10.19                                                ______________________________________                                    

EXAMPLE 214 Preparation of(2S)-(+)-3-[4-(4-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.3 mmol)and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.44 g, 2.3 mmol). Theresulting free base was obtained as a yellow foam. Yield 0.14 g (15%).mp 90°-95° C. FDMS m/e=405 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              71.09     71.22                                                H               5.97      5.98                                                N              10.36     10.62                                                ______________________________________                                    

EXAMPLE 215 Preparation of(2S)-(+)-3-[4-(6-nitro-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 193 from 6-nitro-3-(piperidin-4-yl)-1H-indole (0.49 g, 2.0mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.40 g, 2.1 mmol). Theproduct was isolated as a yellow crystalline solid. Yield 0.34 g (37%).mp 212°-214° C. FDMS m/e=434 (M⁺ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              66.35     66.34                                                H               6.03      6.11                                                N              12.90     12.68                                                ______________________________________                                    

EXAMPLE 216 Preparation of(2S)-(+)-3-[4-(7-methyl-3-indolyl)piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.280 g, 1.48mmol) and 7-methyl-3-(piperidin-4-yl)-1H-indole (0.290 g, 1.39 mmol)using ethanol as reaction solvent. Yield 0.320 g (57%) as a tan foam.FDMS m/e=404 (M+ of free base). α[D]₅₈₉ =11.6 (c=0.98,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              74.41     73.89                                                H               7.24      7.39                                                N              10.41     10.15                                                ______________________________________                                    

EXAMPLE 217 Preparation of(2S)-(+)-3-[4-(6-methyl-3-indolyl)-piperidin-1-yl]-1-(4-indolyloxy)-2-propanol

The title compound was prepared in a fashion similar to that describedin Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.145 g, 0.767mmol) and 6-methyl-3-(piperidin-4-yl)-1H-indole (0.150 g, 0.697 mmol)using ethanol as reaction solvent. Yield 0.140 g (49%) as a tan foam.FDMS m/e=403 (M+ of free base). α[D]₅₈₉ =+3.8 (c=0.98,dimethylsulfoxide).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              74.41     73.57                                                H               7.24      7.08                                                N              10.41     10.42                                                ______________________________________                                    

EXAMPLE 218 Preparation of3-[4-(7-methyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.499 g, 2.4mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.509g, 2.4 mmol) in the presence of 2.0 equivalents of K₂ CO₃ (0.593, 4.3mmol) in dimethylformamide at 90° C. Yield 0.383 g (41%) of a tanpowder. mp 166-169 C. FDMS m/e=405 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              77.89     77.83                                                H               7.06      6.89                                                N              10.90     10.67                                                ______________________________________                                    

EXAMPLE 219 Preparation of3-[4-(6-methyl-3-indolyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-(4-indolyloxy)propane

The title compound was prepared in a fashion similar to that describedin Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.273 g, 2.4mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.279g, 2.4 mmol) in the presence of 2.0 equivalents of K₂ CO₃ (0.593, 4.3mmol) in dimethylformamide at 90° C. Yield 0.167 g (50%) of a tanpowder. mp C. FDMS m/e=405 (M+ of free base).

    ______________________________________                                        analysis       calculated                                                                              found                                                ______________________________________                                        C              77.89     76.91                                                H               7.06      6.82                                                N              10.90     10.48                                                ______________________________________                                    

The following synthesis illustrates a particularly useful and preferredsynthesis of the compound of Example 34 above, which is a particularlyinteresting compound.

Example A Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-propanolsuccinate Preparation a. Preparation of4-hydroxy-4-(3-methoxyphenyl)-1-benzylpiperidine hydrochloride

To a 3 L, 3-necked round-bottomed flask equipped with a magneticstirring bar, condenser, thermocouple and addition funnel were added13.4 g of magnesium turnings. A liter of tetrahydrofuran and 0.07 g ofiodine were added, and the contents was stirred under nitrogen atambient temperature. Approximately 2 mL of 3-bromoanisole was added tothe flask. To the stirring mixture was then added slowly a solution of92.4 g of 3-bromoanisole in 750 mL of tetrahydrofuran, adding thesolution slowly while maintaining the temperature below 66° C. When theaddition was complete, the green-black reaction mixture was stirred at59°-62° C. for an additional hour, and then cooled.

To the mixture was then slowly added 94.6 g of 1-benzyl-4-piperidone,while cooling the flask to keep the temperature below 35° C. Theaddition funnel was rinsed with 30 mL of tetrahydrofuran. Then themixture was cooled to approximately 0° C., and 500 mL of 1N hydrochloricacid was added slowly, holding the temperature below 10° C. The mixturewas then extracted with 1 L of toluene, and the yellow organic layer wasremoved and dried over anhydrous magnesium sulfate. The resulting dryorganic solution was cooled and 1 molar equivalent of hydrogen chloride,dissolved in methanol, was added slowly, maintaining the temperaturebelow 10° C. The slurry was stirred for an hour in the cold andfiltered, and the solids were washed with additional toluene. The wetcake was dried at 40° C. for at least 15 hours to obtain the desiredcompound in potency of 75-90% in different preparations.

Preparation b. Preparation of (S)-(+)-4-(oxiranylmethoxy)-1H-indole

A 3.2 g portion of 4-hydroxy-1H-indole was dissolved in 31 mL ofdimethylformamide in a 50 mL flask equipped with a magnetic stirrer,nitrogen bubbler and thermometer. To it was added 1.27 g of sodiummethoxide and the mixture was stirred until a blue-black solutionresulted. The warm mixture was placed under vacuum for 5 minutes toremove most of the resulting methanol. To the mixture was added 6 g ofoxiranylmethoxysulfonyl-3-nitrobenzene, resulting in an exotherm toabout 37° C. The mixture was stirred at ambient temperature for 1 hour,and was then poured into a separatory funnel containing 55 mL of methylt-butyl ether and 80 mL of water. The mixture was shaken well, and thelayers were separated. The organic layer was removed and the aqueouslayer was extracted with 2×55 mL of methyl t-butyl ether. The organiclayers were combined and back-extracted with 50 mL of 5% aqueous lithiumchloride. The layers were separated again, and the organic layer wasdried with magnesium sulfate and filtered. The organic filtrate wasconcentrated under vacuum to about 15 mL of volume, and was seeded withpure desired product and stirred. The product was crystallized to athick slurry to which 20 mL of heptane was slowly added. The mixture wasstirred for one hour more and filtered, and the filter cake was rinsedwith 3:1 heptane:methyl t-butyl ether, and then with heptane. Theproduct was dried in a vacuum oven at 40° C. to obtain about 3.5 g ofproduct.

Preparation c. Preparation of(2S)-(-)-1-(4-indolyloxy)-3-[4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-2-propanolsuccinate

Three g of 5% palladium/carbon was slurried in 15 mL of water in a 500mL Parr bottle at ambient temperature. To the mixture was added 30 g ofthe product of Preparation a, followed by 70 mL of methanol, and thebottle was placed into the shaker apparatus under 50 psi of hydrogen.The mixture was heated at 50° C. and shaken for 2.5 hours, and thencooled. The mixture was filtered into a 500 mL 3-neck flask equippedwith a condenser, magnetic stirrer, thermometer and temperature control,and the filter cake was rinsed lightly with 5 mL each of methanol andwater. To the filtrate was added 18 mL of 5N aqueous sodium hydroxide,and the cloudy mixture was stirred for 15 minutes. To it was added 16.6g of the product of Preparation b, and the mixture was heated to 60° C.and stirred for 1.5 hours. To the reaction mixture were added 100 mL ofwater and 160 mL of ethyl acetate, and the 2-phase mixture was stirredvigorously. A pH of about 10 was observed. The layers were separated,and the organic layer was warmed to about 60° C. with stirring and 10.2g of succinic acid was added and rinsed in with 20 mL of methanol. Themixture was stirred slowly for about 6 hours with seeding. The slurrywas then cooled in an ice bath, and stirred at a low temperature for 2hours. The solids were removed by filtration and rinsed with 100 mL of3:1 ethyl acetate:methanol and then with 50 mL of ethyl acetate. The drycake was dried at 50° C. overnight. The yield was 35.5 g, at a potencyof 99.1%. The enantiomeric purity was 100%, and the corrected yield was79.3% of theory.

A small second crop of product, amounting to about 3.5 g at a potency of95%, was obtained by concentrating the filtrate to an oil, redissolvingit in a minimum volume of 5:1 ethyl acetate:methanol, and repeatedcooling and filtration.

Serotonin 1_(A) receptor activity

The compounds of the present invention are active at the serotonin 1_(A)receptor, particularly as antagonists and as partial agonists at thatreceptor, and are distinguished by their selectivity. Previously knowncompounds with that activity typically have the disadvantage ofpossessing other non-serotonin related central nervous system activitiesas well. It is now well understood by pharmacologists and physiciansthat pharmaceuticals which have a single physiological activity, orwhich are much more active in the desired activity than in their otheractivities, are much more desirable for therapy than are compounds whichhave multiple activities at about the same dose.

Many other serotonin 1_(A) receptor antagonists typically haveα-adrenergic or β-adrenergic activity as well, and are thereforenonselective for 5HT-1_(A) activity.

The 5HT-1_(A) receptor binding potency of the present compounds has beenmeasured by a modification of the binding assay described by Taylor, etal. (J. Pharmacol. Exp. Ther. 236, 118-125, 1986); and Wong, et al.,Pharm. Biochem. Behav. 46, 173-77 (1993). Membranes for the bindingassay were prepared from male Sprague-Dawley rats (150-250 g). Theanimals were killed by decapitation, and the brains were rapidly chilledand dissected to obtain the hippocampi. Membranes from the hippocampiwere either prepared that day, or the hippocampi were stored frozen(-70°) until the day of preparation. The membranes were prepared byhomogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50mM, pH 7.4 at 22°) using a homogenizer for 15 sec., and the homogenatewas centrifuged at 39800×g for 10 min. The resulting pellet was thenresuspended in the same buffer, and the centrifugation and resuspensionprocess was repeated three additional times to wash the membranes.Between the second and third washes the resuspended membranes wereincubated for 10 min. at 37° to facilitate the removal of endogenousligands. The final pellet was resuspended in 67 mM Tris-HCl, pH 7.4, toa concentration of 2 mg of tissue original wet weight/200 μl. Thishomogenate was stored frozen (-70°) until the day of the binding assay.Each tube for the binding assay had a final volume of 800 μl andcontained the following: Tris-HCl (50 mM), pargyline (10 μM), CaCl₂ (3mM), [³ H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs ofinterest, and membrane resuspension equivalent to 2 mg of originaltissue wet weight, for a final pH of 7.4. The assay tubes were incubatedfor either 10 min. or 15 min. at 37°, and the contents were then rapidlyfiltered through GF/B filters (pretreated with 0.5% polyethylenimine),followed by four one-ml washes with ice-cold buffer. The radioactivitytrapped by the filters was quantitated by liquid scintillationspectrometry, and specific [³ H]8-OH-DPAT binding to the 5-HT1_(A) siteswas defined as the difference between [³ H]8-OH-DPAT bound in thepresence and absence of 10 μM 5-HT.

IC₅₀ values, i.e., the concentration required to inhibit 50% of thebinding, were determined from 12-point competition curves usingnonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, Ill.).

Additional binding assays of some of the present compounds have beencarried out by an assay method which uses a cloned cell line whichexpresses the serotonin 1_(A) receptor, rather than the hippocampalmembranes. Such cloned cell lines have been described by Fargin, et al.,J. Bio. Chem., 264, 14848-14852 (1989), Aune, et al., J. Immunology,151, 1175-1183 (1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 346, 127-137 (1992). Results from the cell line assay aresubstantially in agreement with results from the hippocampal membraneassay.

The efficacy of the compounds of Formulae XI and XIII to inhibit thereuptake of serotonin has been determined by a paroxetine binding essay,the usefulness of which is set out by Wong, et al.,Neuropsychopharmacology, 8, 23-33 (1993). Synaptosomal preparations fromrat cerebral cortex were made from the brains of 100-150 gSprague-Dawley rats which were killed by decapitation. The cerebralcortex was homogenized in 9 volumes of a medium containing 0.32M sucroseand 20 μM glucose. The preparations were resuspended aftercentrifugation by homogenizing in 50 volumes of cold reaction medium (50μM sodium chloride, 50 μM potassium chloride, pH 7.4) and centrifugingat 50,000 g for 10 minutes. The process was repeated two times with a10-minute incubation at 37° C. between the second and third washes. Theresulting pellet was stored at -70° C. until use. Binding of ³H-paroxetine to 5-HT uptake sites was carried out in 2 ml reactionmedium containing the appropriate drug concentration, 0.1 nM ³H-paroxetine, and the cerebral cortical membrane (50 μg protein/tube).Samples were incubated at 37° C. for 30 minutes; those containing 1 μMfluoxetine were used to determine nonspecific binding of ³ H-paroxetine.After incubation, the tubes were filtered through Whatman GF/B filters,which were soaked in 0.05% polyethylenimine for 1 hour before use, usinga cell harvester by adding about 4 ml cold Tris buffer (pH 7.4),aspirating, and rinsing the tubes three additional times. Filters werethen placed in scintillation vials containing 10 ml scintillation fluid,and the radioactivity was measured by liquid scintillationspectrophotometry.

Results of testing representative compounds of Formulae XI and XIII bythe above method showed potent reuptake activity, in many cases activityin the low nM range.

The pharmacological activities which have been described immediatelyabove provide the mechanistic basis for the pharmaceutical utility ofthe compounds described in this document. A number of pharmaceuticalutilities will be described below.

Throughout this document, the person or animal to be treated will bedescribed as the "subject", and it will be understood that the mostpreferred subject is a human. However, it must be noted that the studyof adverse conditions of the central nervous system in non-human animalsis only now beginning, and that some instances of such treatments arecoming into use. For example, fluoxetine, and perhaps other serotoninreuptake inhibitors, are being used in companion animals such as dogsfor the treatment of behavioral problems and the like. Accordingly, useof the present compounds in non-human animals is contemplated. It willbe understood that the dosage ranges for other animals will necessarilybe quite different from the doses administered to humans, andaccordingly that the dosage ranges described below in the section ontobacco withdrawal must be recalculated. For example, a small dog may beonly 1/10th of a typical human's size, and it will therefore benecessary for a much smaller dose to be used. The determination of aneffective amount for a certain non-human animal is carried out in thesame manner described below in the case of humans, and veterinarians arewell accustomed to such determinations.

The activity of the compounds at the serotonin 1_(A) receptor provides amethod of affecting the serotonin 1_(A) receptor which comprisesadministering to a subject in need of such treatment an effective amountof a compound of Formula XII. Reasons for the necessity of affecting the1_(A) receptor will be described in detail below, but in all cases theeffect on the serotonin 1_(A) receptor is brought about through thecompounds' potency as antagonists or partial agonists at that receptor.A subject in need of a modification of the effects of the 5HT-1_(A)receptor is one having one or more of the specific conditions andproblems to be further described, or a condition or problem not yetrecognized as created by an imbalance or malfunction of the 5HT-1_(A)receptor, since research on the central nervous system is presentlyongoing in many fields and newly discovered relationships betweenreceptors and therapeutic needs are continually being discovered. In allcases, however, it is the compounds' ability to affect the serotonin1_(A) receptor which creates their physiological or therapeutic effects.

An effective amount of a compound for affecting the serotonin 1_(A)receptor is the amount, or dose, of the compound which provides thedesired effect in the subject under diagnosis or treatment. The amountis an individualized determination, and physicians are well accustomedto adjusting effective amounts of pharmaceuticals based on observationsof the subject. The effective amount of the present compounds isdiscussed in some detail below, in the discussion about the treatment oftobacco withdrawal symptoms, and that discussion is applicable to thedetermination of the effective amount in all treatment methods.

Further, the activity of compounds of Formula XIII in the inhibition ofthe reuptake of serotonin provides a method of inhibiting the reuptakeof serotonin comprising administering to a subject in need of suchtreatment an effective amount of a compound of that formula. It is nowknown that numerous physiological and therapeutic benefits are obtainedthrough the administration of drugs which inhibit the reuptake ofserotonin. The treatment of depression with drugs of the class of whichfluoxetine is the leader has become perhaps the greatest medicalbreakthrough of the past decade. Numerous other treatment methodscarried out by the administration of the compounds of Formula XIII willbe set out in detail below. Again, the effective amount of a compoundfor the inhibition of serotonin reuptake, or for a specific therapeuticmethod which depends on the inhibition of reuptake, is determined in themanner described below under the heading of smoking withdrawal.

The unique combination of 5HT-1_(A) receptor activity and serotoninreuptake inhibition possessed by the compounds of Formula XIII afford amethod of providing to a subject both physiological activities with asingle administration of a compound of that formula. As discussed in theBackground section of this document, the value of combining the twoeffects has been discussed in the literature, and it is believed thatthe present compounds are the first to provide both physiologicaleffects in a single drug. It is presently believed that the result ofadministration of a compound of Formula XII is to provide physiologicaland therapeutic treatment methods which are typical of those provided bypresently known serotonin reuptake inhibitors, but with enhancedefficacy and quicker onset of action. In addition, of course, all of thephysiological and therapeutic methods provided by compounds which affectthe serotonin 1_(A) receptor are provided by the compounds of FormulaXIII as well. It will be noted that Formula XIII is included in thescope of the 5HT-1_(A) receptor-active compounds of Formula XII.

The activities of Formula XIII compounds at the 5HT-1_(A) receptor andin reuptake inhibition are of comparable potencies, so a singleeffective amount is effective for both purposes.

Further discussion of specific therapeutic methods provided by the dualactivity compounds of Formula XIII, and the diseases and conditionsadvantageously treated therewith, will be provided below.

Tobacco or nicotine withdrawal

It is well known that the chronic administration of nicotine results intolerance and, eventually, dependence. The use of tobacco has becomeextremely widespread in all countries, despite the well known adverseeffects of the use of tobacco in all its forms. Thus, it is clear thattobacco use is extremely habit-forming, if not addictive, and that itsuse provides sensations to the user which are pleasant and welcome, eventhough the user may be fully aware of the drastic long term ill effectsof its use.

Rather recently, vigorous campaigns against the use of tobacco havetaken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

At the present time, probably the most widely used therapy to assist thecessation of tobacco use is nicotine replacement, by the use of nicotinechewing gum or nicotine-providing transdermal patches. It is widelyknown, however, that nicotine replacement is less effective withouthabit-modifying psychological treatment and training.

Thus, the present method of preventing or alleviating the symptomscaused by withdrawal or partial withdrawal from the use of tobacco or ofnicotine comprises the previously discussed method of affecting theserotonin 1_(A) receptor, in that the treatment method comprises theadministration of an effective amount of one of the serotonin 1_(A)receptor-active compounds of Formula XII to the subject. The method ofthe present invention is broadly useful in assisting persons who want tocease or reduce their use of tobacco or nicotine. Most commonly, theform of tobacco use is smoking, most commonly the smoking of cigarettes.The present invention is also helpful, however, in assisting in breakingthe habit of all types of tobacco smoking, as well as the use of snuff,chewing tobacco, etc. The present method is also helpful to those whohave replaced, or partially replaced, their use of tobacco with the useof nicotine replacement therapy. Thus, such subjects can be assisted toreduce and even eliminate entirely their dependence on nicotine in allforms.

A particular benefit of therapy with the present compounds is theelimination or reduction of the weight gain which very often resultsfrom reducing or withdrawing from use of tobacco or nicotine.

It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict subjectswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, light-headedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the subject's use of tobacco or nicotine is adesired result of the present invention and an important aspect of it.

The invention is carried out by administering an effective amount of acompound of Formula XII to a subject who is in need of or carrying out areduction or cessation of tobacco or nicotine use.

The effective amount of compound to be administered, in general, is fromabout 1 to about 100 mg/day; as usual, the daily dose may beadministered in a single bolus, or in divided doses, depending on thejudgment of the physician in charge of the case. A more preferred rangeof doses is from about 5 to about 100 mg/day; other dosage ranges whichmay be preferred in certain circumstances are from about 10 to about 50mg/day; from about 5 to about 50 mg/day; from about 10 to about 25mg/day; and a particularly preferred range is from about 20 to about 25mg/day. It will be understood that the effective amount for a givensubject is always to be set by the judgment of the attending physician,and that the dose is subject to modification based on the size of thesubject, the lean or fat nature of the subject, the characteristics ofthe particular compound chosen, the intensity of the subject's tobaccohabit, the intensity of the subject's withdrawal symptoms, andpsychological factors which may affect the subject's physiologicalresponses. Thus, the effective amount is the amount required to preventor alleviate the symptoms of withdrawal or partial withdrawal in thesubject under treatment.

The effect of the compounds in alleviating the symptoms of nicotinewithdrawal was evaluated in rats by an auditory startle test, which wascarried out as follows.

Procedures for Nicotine Withdrawal Studies

Animals: Male Long Evans rats were individually housed in a controlledenvironment on a 12 hour light-dark cycle and were given free access tofood (Purina Rodent Chow) and water. All treatment groups contained 8-10rats.

Chronic Nicotine Treatment: Rats were anesthetized with halothane andAlzet osmotic minipumps (Alza Corporation, Palo Alto, Calif., Model2ML2) were implanted subcutaneously. Nicotine ditartrate was dissolvedin physiological saline. Pumps were filled with either nicotineditartrate (6 mg/kg base/day) or physiological saline. Twelve daysfollowing implantation of pumps, rats were anesthetized with halothaneand the pumps were removed.

Auditory Startle Response: The sensory motor reactions [auditory startleresponse (peak amplitude Vmax)] of individual rats was recorded usingSan Diego Instruments startle chambers (San Diego, Calif.). Startlesessions consisted of a 5-minute adaptation period at a background noiselevel of 70±3 dBA immediately followed by 25 presentations of auditorystimuli (120±2 dBA noise, 50 ms duration) presented at 8-secondintervals. Peak startle amplitudes were then averaged for all 25presentations of stimuli for each session. Auditory startle respondingwas evaluated daily at 24 hour intervals on days 1-4 following nicotinewithdrawal. Representative compounds were found to attenuate the startleresponse during nicotine withdrawal at very low effective doses.

Combination with reuptake inhibitors

A further application of the compounds of Formula XII is their use incombination with a serotonin reuptake inhibitor to potentiate the actionof those drugs by increasing the availability of serotonin, as well asnorepinephrine and dopamine, in the brain of subjects to whom the drugcombination is administered. Typical and appropriate reuptake inhibitors(SRI) are fluoxetine, duloxetine, venlafaxine, sertraline, milnacipran,citalopram, fluvoxamine and paroxetine. Accordingly, the presentinvention provides a method for potentiating the action of a serotoninreuptake inhibitor, particularly one of the group consisting offluoxetine, duloxetine, venlafaxine, milnacipran, sertraline,citalopram, fluvoxamine and paroxetine, in increasing the availabilityof serotonin, norepinephrine and dopamine in the brain, comprisingadministering said serotonin reuptake inhibitor in combination with thepresent method of affecting the serotonin 1_(A) receptor. The inventionalso provides pharmaceutical compositions which comprise a serotoninreuptake inhibitor in combination with a compound of Formula I, and amethod of treating a pathological condition which is created by or isdependent upon decreased availability of serotonin, dopamine ornorepinephrine, which method comprises administering the same adjunctivetherapy to a subject in need of such treatment.

It will be understood that it is preferred to carry out the presentcombination aspect of the invention with compounds of Formula XII whichare outside the scope of Formula XIII, since the Formula XIII compoundsclearly provide, individually, the benefit of the presently describedcombination. However, it is entirely possible to administer a compoundof Formula XIII, as a special case of the present combination, incombination with a conventional serotonin reuptake inhibitor in order toobtain still further enhanced results in potentiating the serotoninreuptake inhibition.

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U.S. Pat. No. 4,314,081 is an early reference onthe compound. Robertson, et al., J. Med. Chem. 31, 1412 (1988), taughtthe separation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word "fluoxetine" will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word "duloxetine" will be used here to refer toany acid addition salt or the free base of the molecule.

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent.

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moret,et al., Neuropharmacology 24, 1211-19 (1985), describe itspharmacological activities.

Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol. 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol. 2, 225 (1987), and Timmerman, et al., ibid., 239.

Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone0-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen, et al., Brit.J. Pharmacol, 60, 505 (1977); and De Wilde, et al., J. Affective Disord.4, 249 (1982); and Benfield, et al., Drugs 32, 313 (1986).

Sertraline, 1-(3,4-dichlorophenyl)-4-methylaminotetralin, is disclosedin U.S. Pat. No. 4,536,518.

Paroxetine,trans-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978);Hassan, et al., Brit. J. Clin. Pharmacol. 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand. 71, 249 (1985); and Battegay, et al.,Neuropsychobiology 13, 31 (1985).

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

In general, combinations and methods of treatment using fluoxetine orduloxetine as the SRI are preferred.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein, and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

The dosages of the drugs used in the present combination must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the subject,including diseases other than that for which the physician is treatingthe subject. General outlines of the dosages, and some preferred humandosages, can and will be provided here. Dosage guidelines for some ofthe drugs will first be given separately; in order to create a guidelinefor any desired combination, one would choose the guidelines for each ofthe component drugs.

Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day;

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day;

Citalopram: from about 5 to about 50 mg once/day; preferred, from about10 to about 30 mg once/day;

Fluvoxamine: from about 20 to about 500 mg once/day; preferred, fromabout 50 to about 300 mg once/day;

Paroxetine: from about 5 to about 100 mg once/day; preferred, from about50 to about 300 mg once/day.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of SRI according to the spirit of theabove guideline, and choosing a dosage of the compound of Formula XII inthe ranges taught above.

The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of Formula XII in anymanner which provides effective levels of the two compounds in the bodyat the same time. All of the compounds concerned are orally availableand are normally administered orally, and so oral administration of theadjunctive combination is preferred. They may be administered together,in a single dosage form, or may be administered separately.

However, oral administration is not the only route or even the onlypreferred route. For example, transdermal administration may be verydesirable for subjects who are forgetful or petulant about taking oralmedicine. One of the drugs may be administered by one route, such asoral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the subject and the caregiver.

It is particularly preferred, however, for the adjunctive combination tobe administered as a single pharmaceutical composition, and sopharmaceutical compositions incorporating both a SRI and a compound ofFormula XII are important embodiments of the present invention. Suchcompositions may take any physical form which is pharmaceuticallyacceptable, but orally usable pharmaceutical compositions areparticularly preferred. Such adjunctive pharmaceutical compositionscontain an effective amount of each of the compounds, which effectiveamount is related to the daily dose of the compounds to be administered.Each adjunctive dosage unit may contain the daily doses of bothcompounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the subject would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

As stated above, the benefit of the adjunctive therapy is its ability toaugment the increase in availability of serotonin, norepinephrine anddopamine caused by the SRI compounds, resulting in improved activity intreating the various conditions described below in detail. The increasein availability of serotonin is particularly important and is apreferred aspect of the invention. Further, the invention provides amore rapid onset of action than is usually provided by treatment withthe SRI alone.

The therapeutic applications of the treatment method, described atlength above, comprising the combined administration of a serotoninreuptake inhibitor and a compound of Formula XII, and the methodcomprising the administration of a compound of Formula XIII, aresubstantially the same, since the effect of both methods of treatment isto potentiate the action of serotonin reuptake inhibition. Accordingly,specific methods of treatment, and the conditions and diseases to betreated therewith, of both methods will be discussed as one, in thefollowing section.

Preferred pathological conditions to be treated by the present treatmentmethods include depression, bulimia, obsessive-compulsive disease andobesity. Another preferred condition more specific to combinationsincluding preferably duloxetine but also venlafaxine and milnacipran isurinary incontinence.

Depression in its many variations has recently become much more visibleto the general public than it has previously been. It is now recognizedas an extremely damaging disorder, and one that afflicts a surprisinglylarge fraction of the human population. Suicide is the most extremesymptom of depression, but millions of people, not quite so drasticallyafflicted, live in misery and partial or complete uselessness, andafflict their families as well by their affliction. The introduction offluoxetine was a breakthrough in the treatment of depression, anddepressives are now much more likely to be diagnosed and treated thanthey were only a decade ago. Duloxetine is in clinical trials for thetreatment of depression and is likely to become a marketed drug for thepurpose.

Depression is often associated with other diseases and conditions, orcaused by such other conditions. For example, it is associated withParkinson's disease; with HIV; with Alzheimer's disease; and with abuseof anabolic steroids. Depression may also be associated with abuse ofany substance, or may be associated with behavioral problems resultingfrom or occurring in combination with head injuries, mental retardationor stroke. Depression in all its variations is a preferred target oftreatment with the present adjunctive therapy method and compositions.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the victim's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted subject may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

Obesity is a frequent condition in the American population. It has beenfound that fluoxetine will enable an obese subject to lose weight, withthe resulting benefit to the circulation and heart condition, as well asgeneral well being and energy.

Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles. Duloxetine controls both types of incontinence, or bothtypes at once, and so is important to the many who suffer from thisembarrassing and disabling disorder.

The present treatment methods are useful for treating many otherdiseases, disorders and conditions as well, as set out below. In manycases, the diseases to be mentioned here are classified in theInternational Classification of Diseases, 9th Edition (ICD), or in theDiagnostic and Statistical Manual of Mental Disorders, 3rd VersionRevised, published by the American Psychiatric Association (DSM). Insuch cases, the ICD or DSM code numbers are supplied below for theconvenience of the reader.

depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82, 293.83,310.10, 318.00, 317.00

migraine

pain, particularly neuropathic pain

bulimia, ICD 307.51, DSM 307.51

premenstrual syndrome or late luteal phase syndrome, DSM 307.90

alcoholism, ICD 305.0, DSM 305.00 & 303.90

tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

panic disorder, ICD 300.01, DSM 300.01 & 300.21

anxiety, ICD 300.02, DSM 300.00

post-traumatic syndrome, DSM 309.89

memory loss, DSM 294.00

dementia of aging, ICD 290

social phobia, ICD 300.23, DSM 300.23

attention deficit hyperactivity disorder, ICD 314.0

disruptive behavior disorders, ICD 312

impulse control disorders, ICD 312, DSM 312.39 & 312.34

borderline personality disorder, ICD 301.83, DSM 301.83

chronic fatigue syndrome

premature ejaculation, DSM 302.75

erectile difficulty, DSM 302.72

anorexia nervosa, ICD 307.1, DSM 307.10

disorders of sleep, ICD 307.4

autism

mutism

trichotillomania

Further, the compounds of Formula XII are particularly useful foralleviating the symptoms of smoking cessation or nicotine withdrawalwhen administered in combination with a serotonin reuptake inhibitor.The SRI's to be used in this treatment method, and the administrationmethods and formulations, are as described above. The use of the presentcompounds with SRI's in subjects striving to stop use of tobacco ornicotine provides surprisingly complete alleviation of the usual painfuland damaging symptoms of such subjects, including nervousness,irritability, craving, excessive appetite, anxiety, depression in manyforms, inability to concentrate, and the like. Thus, the control orelimination of weight gain in the subject undergoing withdrawal from orreduction of tobacco or nicotine use is a particularly valuable andpreferred benefit of the use of a present compound in combination withan SRI.

Therapeutic applications

The compounds of Formula XII are useful for other important therapeuticpurposes, as well as in combination with SRIs and in nicotine withdrawalor smoking cessation cases. In particular, the compounds are valuablefor binding, blocking or modulating the serotonin 1_(A) receptor, andfor the treatment or prophylaxis of conditions caused by or influencedby defective function of that receptor. In particular, the compounds areuseful for antagonism at the serotonin 1_(A) receptor and accordinglyare used for the treatment or prevention of conditions caused by oraffected by excessive activity of that receptor.

More particularly, the compounds are useful in the treatment of anxiety,depression, hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, appetite disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine.

Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02. A furtherparticularly noted disorder is depression and the group ofdepression-related disorders, which are discussed above in thediscussion of adjunctive therapy with SRIs.

The unique combination of pharmacological properties possessed by thecompounds of Formula XIII permit those compounds to be used in a methodof simultaneously treating anxiety and depression. The anxiety portionof the combined syndrome is believed to be attacked by the 5HT-1_(A)receptor-affecting property of the compounds, and the depression portionof the condition is believed to be addressed by the reuptake inhibitionproperty. Thus, administration of an effective amount, as discussedabove, of a compound of Formula XIII will provide treatment for thecombined condition.

Pharmaceutical compositions

It is customary to formulate pharmaceuticals for administration, toprovide control of the dosage and stability of the product in shipmentand storage, and the usual methods of formulation are entirelyapplicable to the compounds of Formula I. Such compositions, comprisingat least one pharmaceutically acceptable carrier, are valuable and novelbecause of the presence of the compounds of Formula I therein. Althoughpharmaceutical chemists are well aware of many effective ways toformulate pharmaceuticals, which technology is applicable to the presentcompounds, some discussion of the subject will be given here for theconvenience of the reader.

The usual methods of formulation used in pharmaceutical science and theusual types of compositions may be used, including tablets, chewabletablets, capsules, solutions, parenteral solutions, intranasal sprays orpowders, troches, suppositories, transdermal patches and suspensions. Ingeneral, compositions contain from about 0.5% to about 50% of thecompound in total, depending on the desired dose and the type ofcomposition to be used. The amount of the compound, however, is bestdefined as the effective amount, that is, the amount of each compoundwhich provides the desired dose to the subject in need of suchtreatment. The activity of the compounds do not depend on the nature ofthe composition, so the compositions are chosen and formulated solelyfor convenience and economy. Any compound may be formulated in anydesired form of composition. Some discussion of different compositionswill be provided, followed by some typical formulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acidic contents of the stomach. Such formulations arecreated by coating a solid dosage form with a film of a polymer which isinsoluble in acidic environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the subject consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some subjects.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with pores through whichthe drugs are pumped by osmotic action.

The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                       Quantity                                                                      (mg/capsule)                                                   ______________________________________                                        Example 63        20 mg                                                       Starch, dried    200 mg                                                       Magnesium stearate                                                                              10 mg                                                       Total            230 mg                                                       ______________________________________                                    

Formulation 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                         Quantity                                                                      (mg/capsule)                                                 ______________________________________                                        Example 89          10 mg                                                     Cellulose, microcrystalline                                                                      400 mg                                                     Silicon dioxide, fumed                                                                            10 mg                                                     Stearic acid        5 mg                                                      Total              425 mg                                                     ______________________________________                                    

The components are blended and compressed to form tablets each weighing425 mg.

Formulation 3

Tablets, each containing 10 mg of active ingredient, are made asfollows:

    ______________________________________                                        Example 78           10 mg                                                    Starch               45 mg                                                    Microcrystalline cellulose                                                                         35 mg                                                    Polyvinylpyrrolidone  4 mg                                                    (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                        4.5 mg                                                   Magnesium stearate   0.5 mg                                                   Talc                  1 mg                                                    Total                100 mg                                                   ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl-pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 100 mg.

Formulation 4

Capsules, each containing 30 mg of active ingredient, are made asfollows:

    ______________________________________                                        Example 196        30 mg                                                      Starch             59 mg                                                      Microcrystalline cellulose                                                                       59 mg                                                      Magnesium stearate  2 mg                                                      Total              150 mg                                                     ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation 5

Suppositories, each containing 5 mg of active ingredient, are made asfollows:

    ______________________________________                                        Example 126                5 mg                                               Saturated fatty acid glycerides                                                                       2,000 mg                                              Total                   2,005 mg                                              ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 6

Suspensions, each containing 10 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        Example 154              10     mg                                            Sodium carboxymethyl cellulose                                                                         50     mg                                            Syrup                    1.25   ml                                            Benzoic acid solution    0.10   ml                                            Flavor                   q.v.                                                 Color                    q.v.                                                 Purified water to total  5      ml                                            ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An intravenous formulation may be prepared as follows:

    ______________________________________                                        Example 189           10     mg                                               Isotonic saline       1,000  ml                                               ______________________________________                                    

We claim:
 1. A compound of the formula ##STR46## wherein r is 0-4;s is0-1; D is a residue which combines with the carbon atoms to which it isattached to complete a pyrrolyl group; wherein X is hydrogen, phenyl,hydroxy or methoxy; provided that X is hydrogen or phenyl when r is 0; Ris ##STR47## R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl; or R⁵ is C₁ -C₃ alkylsubstituted with benzodioxinyl or benzodioxolyl,substituted on thephenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups; or R⁵is pyridinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl, pyrazinyl,quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl,substituted with0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy or halo groups; or R⁵is ##STR48## B is oxygen or sulfur; Y is a residue which combines withthe atoms to which it is attached to complete a triazolyl, imidazolyl,thiazolyl or pyrrolyl ring;or a pharmaceutically acceptable saltthereof.
 2. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or excipient and a compound of claim
 1. 3. A methodof affecting the serotonin 1A receptor which comprises administering toa subject in need of such treatment an effective amount of a compound ofthe formula ##STR49## wherein r is 0-4;s is 0-1; D is a residue whichcombines with the carbon atoms to which it is attached to complete apyrrolyl group; wherein X is hydrogen, phenyl, hydroxy or methoxy;provided that X is hydrogen or phenyl when r is 0; R is ##STR50## R⁵ isC₁ -C₆ alkyl or C₁ -C₄ acyl; or R⁵ is C₁ -C₃ alkyl substituted withphenyl, benzodioxinyl or benzodioxolyl,substituted on the phenyl ringwith 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups; or R⁵ is pyridinyl,phenyl, naphthyl, tetralinyl, pyrimidinyl, indolyl, benzofuryl,benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl orquinazolinyl,substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃alkoxy or halo groups; or R⁵ is ##STR51## B is oxygen or sulfur; Y is aresidue which combines with the atoms to which it is attached tocomplete a triazolyl, imidazolyl, thiazolyl or pyrrolyl ring;or apharmaceutically acceptable salt thereof.
 4. A method of inhibiting thereuptake of serotonin which comprises administering to a subject in needof such treatment an effective amount of a compound of formula ##STR52##wherein r is 0-3;X is hydrogen or hydroxy; R is ##STR53## R⁵ is phenyl,phenyl-C₁ -C₃ alkyl, or diphenyl-C₁ -C₃ alkyl, substituted with 1-2halo, C₁ -C₃ alkoxy or trifluoromethyl groups;or a pharmaceuticallyacceptable salt thereof.
 5. A method of claim 4 wherein the serotonin 1Areceptor of the subject is also affected by the compound.
 6. A method ofpreventing or alleviating the symptoms caused by withdrawal or partialwithdrawal from the use of tobacco or of nicotine which comprises themethod of claim
 3. 7. A method of treating depression which comprisesthe method of claim
 4. 8. A method of treating anxiety which comprisesthe method of claim
 3. 9. A method of treating both anxiety anddepression which comprises the method of claim
 4. 10. A method oftreating a condition chosen from the group consisting of hypertension,cognitive disorders, psychosis, sleep disorders, gastric motilitydisorders, sexual dysfunction, brain trauma, memory loss, eatingdisorders and obesity, substance abuse, obsessive-compulsive disease,panic disorder and migraine, comprising the method of claim
 3. 11. Amethod of treating a condition chosen from the group consisting ofobsessive-compulsive disease, obesity, migraine, pain, particularlyneuropathic pain, bulimia, premenstrual syndrome or late lutealsyndrome, alcoholism, tobacco abuse, panic disorder, anxiety,post-traumatic syndrome, memory loss, dementia of aging, social phobia,attention-deficit hyperactivity disorder, disruptive behavior disorders,impulsive control disorders, borderline personality disorder, chronicfatigue syndrome, premature ejaculation, erectile difficulty, anorexianervosa, disorders of sleep, autism, mutism and trichotilomania,comprising the method of claim
 4. 12. A method of potentiating theaction of a serotonin reuptake inhibitor in increasing the availabilityof serotonin, norepinephrine and dopamine in the brain, comprisingadministering to a subject in need of such treatment a serotoninreuptake inhibitor in combination with the method of claim
 3. 13. Amethod of claim 6 wherein a serotonin reuptake inhibitor is alsoadministered to the subject.
 14. A compound of claim 1 wherein X ishydrogen or hydroxy; s is 0; and r is 0-3.
 15. A method of claim 3wherein the compound is a compound wherein X is hydrogen or hydroxy; sis 0; and r is 0-3.
 16. A method of treating anxiety which comprises themethod of claim
 15. 17. A method of treating a condition chosen from thegroup consisting of hypertension, cognitive disorders, psychosis, sleepdisorders, gastric motility disorders, sexual dysfunction, brain trauma,memory loss, eating disorders and obesity, substance abuse,obsessive-compulsive disease, panic disorder and migraine, comprisingthe method of claim
 15. 18. A method of preventing or alleviating thesymptoms caused by withdrawal or partial withdrawal from the use oftobacco or of nicotine which comprises the method of claim
 15. 19. Amethod of potentiating the action of a serotonin reuptake inhibitor inincreasing the availability of serotonin, norepinephrine and dopamine inthe brain, comprising administering to a subject in need of suchtreatment a serotonin reuptake inhibitor in combination with the methodof claim 15.